Notes on Hypothesis Making in Medicine: Opiates and Opioids as a Unifying Framework for Mental Illness

This piece of work represents a continuation of a multivalent piece of interdisciplinary work which extends back over the last twenty years.  In this social document two main purposes are being addressed, the first one being continuing a study of science and it’s information tools exploring the basis of how hypotheses can be constructed and tested so that the reader may get some sense of where an idea sits on a scale of increasingly or decreasingly reliable knowledge.



In this context this article is to share a public document which is a part of the process of ‘verbatim science’, a methodology developed by this author in order to create a forensic study of a given subject assembling and annotating excerpts from peer reviewed science publications. In order to document the process developed around the information tools which are used, the mid-process artifact of the research effort is presented here. Below what you can find is the transplanted work of a manuscript cut into themed bricolage and ordered according to emergent threads.


The work which has emerged from an accumulative research process over time has suggested particular patterns of biochemical events that may – or may not – offer an overarching biological thesis for phenomena relating to states of mind commonly associated with mental illness. The literature suggests that the non-analgesic properties of opiates and opioids may be playing key roles in altered states of consciousness and apprehension.


The verbatim science document you see below is the output of an assemblage of referenced facts sourced from peer reviewed medical science, constructed in the open source mindmapping software Xmind.  It is indexed with anchored hyperlinks which facilitate the reader being able to navigate around the complexity of the information. You will notice that as a working document the references have been marked out but the bibliography of references has not been constructed; this is because it is a work in progress and the aim of this article is to describe and document a methodology.


In the process of researching and aggregating work which fleshes out a subject of study, the aim is to group concise information in themed groups where like facts have been stored. As the verbatim science methodology aims to be forensic the language is quoted exactly and not treated so that minimal distortions occur in the re-authoring of discoveries and observations. The maintaining of original form both acts as a more accurate atlas of the subject of study and it offers a means of getting back to the original documents efficiently should the need arise.


The next stage of this verbatim science project is to supplement the information arranged, order the information within the groups into some sensible forms of grouping and/or sequencing, and attempt to falsify the existing information by exploiting academic-librarian means of inference before assembling the final bibliography, contents page, index and overarching narratives.


Rationales for a Biochemistry of Mad Studies

The second major purpose of this project is addressing the study of the physicality of mental illness, altered states of mind, and madness in such a way that it also makes sense in relation to the social models of mental illness and sociological accounts of altered and/or damaged states of mind.  All knowledge seems to be controversial in some quarters; the sociology of knowledge is somewhat bound up with identity, status, territorialism, and politicisation. The particular focus of where psychiatry and psychology meet attracts conflicting opinion especially as cultures of dichotomy clash in tendencies of dualism which are more habit than wisdom.


The materialist perspective not uncommonly contrasts and generates friction with the perspective of idealism and camps are created as identities are drawn from where individuals, institutions, cultures and practices stake out the boundaries of what is considered to be correct – right; that is to say, to a certain extent each person from their own position will have some sense that their apprehension of phenomena better represents the truth – that they embody the orthodox, even if other people may not subscribe to their view.


This work is not an attempt to resolve for others these tensions but continue a project in order to find practical answers which relate usefulness to the author. This public document is in part a means to develop the tools and apparatus necessary to reach towards a falsifiable theory of some madnesses. In this project science is treated as a primary tool of discovery, and to question the bounded nature of who gets to engage with medicine is necessary for the individual for whom their health and wellbeing is at stake.


In short, medicine and the physical sciences are not the exclusive domains of the institutions which are charged with their societal care, they are co-owned by each person as any public commons is. There is a view of medicine which is innate to the sovereign individual where the human rights are not alienated to those privileged with status; it is a distinct Lockean perspective that both assumes responsibility and inalienable dignities, and by extension sees these in all persons and peoples.


Whilst the trained medic is an important figure to consult as an agent, the person seeking advice and insight has equal value and importance as the principle. When a medic is trained and functions in and under a rubric, there comes a time when questioning said rubric becomes neccessary for progress – in particular, in situations where the rubric demonstrates no effective solutions. In such situations taking science into one’s own hands is acceptible when the tenets of science are adhered to.


In other words, when a rubric does not work it is acceptable to seek out alternative courses of action. In relation to the field of psychiatry there is plenty of scope for this kind of thinking seeing it fails considerably both in articulating the phenomena and presenting appropriate solutions.  For a discussion of this please see the article Critical Analysis of the Medical Institution With Special Focus on Madness.


The question is helpfully negotiated by the notion of appropriate behaviour of context which leads to health and wellbeing.  Personal investment in the science of medicine and reaching towards better health and wellbeing is an appropriate behaviour in the context of ailing which someone might be suffering.


For example, asking to see the science behind a diagnosis and the use of a particular medication to treat said diagnosis should be normative rather than diminishingly obscure in occurrence. In many cases engagement with and education of medicine would improve adherence and outcomes should the patient be supported to expand their understandings; in such situations the responsibilities often loaded upon the medic would not go through a transference carrying with it liabilities.


What follows are the colllected notes on the function and biology of opiates and opioids

Opiate System

1. Endogenous Opioids 3

1.1. Metabolic detoxification of Opioids 6

1.1.1. Phase 1 Detoxification 9 Cytochrome P450 enzyme CYP3A4 12 Cytochrome P450 enzyme CYP2D6 15

1.1.2. Phase 2 Detoxification 18 UDP-Glucuronosyltransferase-2B7 UGT2B7 19

1.2. Enkephalins in the Brain 19

1.2.1. Enkephalins and Dopa pathways 20

1.2.2. Antipsychotics Raise Enkephalin Levels 20

1.2.3. Tricyclic Antidepressants Raise Enkephalin Levels 22

1.2.4. Diazepam Increases Enkephalins in Hypothalamus 23

1.2.5. Aromatic Neurotransmitters Inhibit Enkephalin Degradation 24

1.3. Endorphins in the Pituitary 24

1.3.1. Endorphin Excess Theory 26 Naloxone in Schizophrenia 30 Endorphins in Schizophrenia 31 Hemodialysis in Schizophrenia 36

1.3.2. Endorphin Deficit Theory 42 Cortisol in Depression 42 Endorphin Deficiency in Schizophrenia 44 Endorphin Deficiency in Depression 45

1.3.3. Circadian Rythme to Beta Endorphin 51

1.3.4. Endorphins Acting on the Hypothalamus 52

1.3.5. Stress leads to release of ACTH and beta-endorphin 52

1.3.6. Endorphins, Pain and Analgesia 53

1.3.7. Electrostimulation, Acupuncture and Opioids 61

1.4. Neurotransmission 61

1.4.1. Opiates Increase Dopa, Antipsychotics and Adrenal Activity 63 Tardive Dyskinesia and parkinsons 70

1.4.2. Opiates increase serotonin activity 71

1.4.3. Phenylketonuria: phenylalanine and β-endorphin were significantly correlated 72

1.5. Neuroendocrine interactions with Opioid Molecules 73

1.5.1. Growth Hormone and Prolactin 77

1.5.2. Estrous Cycle 79

1.5.3. Substance P as an opioid 80

1.5.4. Testosterone and Lutinizing Hormone 80

1.5.5. Prolactin 81

1.5.6. ACTH 89

1.5.7. Lutinizing Hormone 92

1.5.8. Vasopressin 93

2. Exogenous Opioids 93

2.1. Heroin, Morphine, and Methadone in Psychiatric Self medication 93

2.2. Ethanol 97

2.2.1. Tetrahydro Iso Quinolines 98

2.3. Neuroleptics 99

2.4. Nitric Oxide 101

3. Opiate Influences on Behaviour 103

3.1. Opioids, Feeding and Drinking 106

3.2. Opiates in Dementia 108

3.3. Opiates in Learning, Memory and Cognition 109

3.4. Opiates and Increased Emotionality 114

3.5. Opiates in addiction 115

3.5.1. LSD in alcohol use disorder 115

3.6. Stress and Opioids 116

3.6.1. Shock 116

3.7. Opioids and Sleep 117

4. Opiate Receptors 117

4.1. Inactivation of Sulfhydryl Groups by N-ethylmaleimide (NEM) 119

4.2. Changes in Opiate Receptors Induced by Sodium 119

4.3. Cyclic AMP and Prostaglandin release after receptor activation 120

4.3.1. Opioid Stimulation of PGE1 Biosynthesis 120

4.3.2. Alcohol Stimulation of PGE1 Biosynthesis 121

4.4. Lithium, Mania and Opiates 122

4.5. Opiate Receptor Blockers 124

4.5.1. Naloxone 126

4.5.2. Naltrexone 137

As the pharmacologist would remind us, every drug has at least two actions: “The one you know about and the one you don’t.”



The discovery of opiate receptors in the early 1970s triggered a search for the endorphins and such endogenous opiate ligands.

In vitro demonstration of opiate receptors has shown that these receptors are ubiquitous in the higher animals, having been found in man, in all vertebrates so far studied, and, in some invertebrates.

Endorphins and enkephalins are generally stored in the neurons and distributed throughout the CNS. Anatomical distribution indicates the presence of two opioid systems: the endorphins and the enkephalins.


It was already clear that brain opiates probably had both narcotic and nonnarcotic effects and that the latter might be of greater significance. This concept of the dissociative effects of endogenous opiates has been supported by several groups.


Abnormal release of naturally occurring opioids is being implicated in different disease states by several medical researchers.


  1. Endogenous Opioids

Like β-Lipotropin, the larger endorphins are predominantly found in the pituitary gland. The enkephalins, on the other hand, are found almost exclusively in the brain.



Several studies have indicated that the endorphins may not be the only endogenous opioid ligands. A number of nonpeptide morphine-like materials have been identified in the brain of various species (Gintzler et al., 1976, 1978; Blume et al., 1977), in human CSF (Shorr et al., 1978), as well as in the blood and small intestine of various species (Schulz et al., 1977b).


Biochemical evidence indicates that endorphins and enkephalins may have dual roles as neurohormones and neurotransmitters.

The endogenous opioids belong to two families of peptides:

(1) short peptides of 5-9 amino acids of which Met- and Leu-enkephalin are the prototypes; and

(2) longer peptides derived from the trophic pituitary hormone beta-lipotropin, of which beta-Endorphin and alpha-endorphin are the prototypes.

Peptides from both families seem to act as neurotransmitters and as neurohormones.


The discovery of opiate receptors in the human brain sparked the search for their endogenous ligands. Independently, Terenius and Wahlstrom (1975) and Hughes (1975) isolated the endogenous ligands. The important ligands are the two pentapeptides Met- and Leu-enkephalin (Hughes et al., 1975) as well as beta-endorphin (beta-lipotropin 61-91).

The discovery of the endorphins resulted from two observations:

1. The mammalian CNS contains binding sites with a high affinity for morphine and related compounds and which are insensitive to any other known neurotransmitter (Pert and Snyder, 1973; Simon et al., 1973; Terenius, 1973).

2. Pain can be alleviated in test animals by electrical stimulation of certain brain areas. This stimulation-induced analgesia can be antagonized by morphine antagonists, e.g., naloxone (Mayer et al., 1971; Akil et al., 1976, 1978).

These observations suggested the existence of an endogenous ligand for the so-called opiate receptors. Two compounds have been isolated from brain tissue (Hughes et al., 1975) and have been identified as pentapeptides, termed enkephalins: Met-enkephalin and Leu-enkephalin.

The structure of Met-enkephalin is also present in the pituitary hormone β-Lipotropin (β-LPH) which consists of 91 amino acids. This hormone was first isolated by Li (1964) from the anterior pituitary lobe. The molecular structure of Met-enkephalin proved to correspond with that of β-Lipotropin 61 – 65.

Apart from the pentapeptides, Met-enkephalin and Leu-enkephalin, other morphinomimetic substances have been isolated from hypothalamic-pituitary extracts which are incorporated in the β-Lipotropin structure and can probably be generated from this hormone.

Fragment 61-91 of β-Lipotropin (the so-called C-fragment) was the first to be isolated (Bradbury et al., 1976; Li and Chung, 1976). This C-fragment is now known as beta-Endorphin.

Two additional endorphins have been isolated: LPH 61-77 (y- endorphin)) and a-endorphin (β-Lipotropin 61 – 76) (Guillemin, 1977).

Like β-Lipotropin, the larger endorphins are predominantly found in the pituitary gland. The enkephalins, on the other hand, are found almost exclusively in the brain.



The Met-enkephalin sequence was identified as residues 61-65 of Beta-Lipotropin (Beta-LPH), a peptide composed of 91 amino acids isolated earlier from the pituitary gland. Beta-LPH was identified as a cleavage product of the 31K glycoprotein, pro-opiocortin, which is the precursor also for Adrenocorticotropic hormone (ACTH) and β-melanocyte-stimulating hormone (Beta-MSH).

The probable precursor of Leu-enkephalin, which is not a cleavage product of Beta-LPH, was identified in extracts of hypothalamus and that brain contains in addition Beta-endorphin (Beta-LPH 61-91), ACTH, as well as several other unidentified opioid peptides.

The name endorphin was adopted for all endogenous opiate-like peptides. The pools of different opioids are not identical.



Sites of production of enkephalins, and endorphins containing up to 31 amino acid residues of Beta-LPH, closely follow the previously known distribution of opiate receptors in brain.

In the pituitary, it is the neurointermediate lobe that contains significant amounts of enkephalins. The peptides are concentrated in nerve fibers projecting from the hypothalamus to the pars nervosa, namely from the paraventricular and supraoptic nuclei. From this localization, a role was proposed for the hypothalamic enkephalins in the regulation of vasopressin and other magnocellular hormonal secretion.

Opposite to the enkephalins, Beta-endorphin predominates in the anterior pituitary. Concentrations of Beta-endorphin in the hypothalamus and in the hypophyseal portal blood are extremely high.

In monkeys, endorphin levels are a thousand times higher in the portal than in the peripheral blood. The median eminence, which is rich in pituitary hormone releasing factors, contains high levels of endorphins. It is hypothesized that corticotropin releasing factor (CRF) from the hypothalamus has regulatory effect not only on ACTH but also on Beta-endorphin release from the pituitary.

Endorphins increase the secretion of some pituitary hormones, e.g., prolactin, GH, vasopressin, and inhibit others, e.g., LH, FSH.



    1. Metabolic detoxification of Opioids

The more prolonged and profound actions of longer-chain peptides of the beta-endorphin group compared to shorter-chain enkephalins (Kosterlitz, 1976) are attributable to their resistance to peptidase enzymes.

Also enhanced levels of endorphins may result either from the delayed enzymatic degradation of opioid peptides or by unknown factor(s) that would interfere with the normal biochemical action of enzymes responsible for the catabolism of neuropeptides.


The highest Met-enkephalin-degrading activities (448-377 nmole/mg protein per 10 min) were found in tissue extracts of some subcortical nuclei: the substantia nigra > anterior thalamus > septal area > globus pallidus > caudate nucleus > hypothalamus; the lowest activity measured was in Broca’s gyrus (138 nmole/mg protein per 10 min).


Metabolism refers to the process of biotransformation by which drugs are broken down so that they can be eliminated by the body. Some drugs perform their functions and then are excreted from the body intact, but many require metabolism to enable them to reach their target site in an appropriate amount of time, remain there an adequate time, and then be eliminated from the body.

Opioid metabolism results in the production of both inactive and active metabolites. The metabolites may be more potent than the parent compound. Both phase 1 and 2 metabolites can be active or inactive. The process of metabolism ends when the molecules are sufficiently hydrophilic to be excreted from the body.

Altered metabolism in a patient or population can result in an opioid or staying in the body too long and producing toxic effects.

Opioid metabolism takes place primarily in the liver, which produces enzymes for this purpose.

Enymes promote 2 forms of metabolism: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).

Most opioids undergo extensive first-pass metabolism in the liver before entering the systemic circulation. First-pass metabolism reduces the bioavailability of the opioid. Opioids are typically lipophilic, which allows them to cross cell membranes to reach target tissues. Drug metabolism is ultimately intended to make a drug hydrophilic to facilitate its excretion in the urine.

Phase 1 metabolism typically subjects the drug to oxidation or hydrolysis. It involves the cytochrome P450 (CYP) enzymes, which facilitate reactions that include N-, O-, and S-dealkylation; aromatic, aliphatic, or N-hydroxylation; N-oxidation; sulfoxidation; deamination; and dehalogenation.

Phase 2 metabolism conjugates the drug to hydrophilic substances, such as glucuronic acid, sulfate, glycine, or glutathione.

The most important phase 2 reaction is glucuronidation, catalyzed by the enzyme uridine diphosphate glucuronosyltransferase (UGT). Glucuronidation produces molecules that are highly hydrophilic and therefore easily excreted.

Opioids undergo varying degrees of phase 1 and 2 metabolism. Phase 1 metabolism usually precedes phase 2 metabolism, but this is not always the case.

Each of these opioids has substantial interaction potential with other commonly used drugs that are substrates, inducers, or inhibitors of the CYP3A4 enzyme (Table 2).24,25 Administration of CYP3A4 substrates or inhibitors can increase opioid concentrations, thereby prolonging and intensifying analgesic effects and adverse opioid effects, such as respiratory depression. Administration of CYP3A4 inducers can reduce analgesic efficacy.10,11,16 In addition to drugs that interact with CYP3A4, bergamottin (found in grapefruit juice) is a strong inhibitor of CYP3A4,26 and cafestol (found in unfiltered coffee) is an inducer of the enzyme.

Induction of CYP3A4 may pose an added risk in patients treated with tramadol, which has been associated with seizures when administered within its accepted dosage range.

This risk is most pronounced when tramadol is administered concurrently with potent CYP3A4 inducers, such as carbamazepine, or with selective serotonin reuptake inhibitors, tricyclic antidepressants, or other medications with additive serotonergic effects.

The CYP2D6 enzyme is entirely responsible for the metabolism of hydrocodone, codeine, and dihydrocodeine to their active metabolites (hydromorphone, morphine, and dihydromorphine, respectively), which in turn undergo phase 2 glucuronidation.

These opioids (and to a lesser extent oxycodone, tramadol, and methadone) have interaction potential with selective serotonin reuptake inhibitors, tricyclic antidepressants, β-blockers, and antiarrhythmics; an array of other drugs are substrates, inducers, or inhibitors of the CYP2D6 enzyme.

Smith H. S. (2009). Opioid metabolism. Mayo Clinic proceedings, 84(7), 613–624. doi:10.1016/S0025-6196(11)60750-7

      1. Phase 1 Detoxification

Phase 1 metabolism of opioids mainly involves the CYP3A4 and CYP2D6 enzymes.

Cytochromes P450 (CYPs) are a family of enzymes containing heme as a cofactor that function as monooxygenases

The CYP3A4 enzyme metabolizes more than 50% of all drugs; consequently, opioids metabolized by this enzyme have a high risk of drug-drug interactions.

The CYP2D6 enzyme metabolizes fewer drugs and therefore is associated with an intermediate risk of drug-drug interactions.

Drugs that undergo phase 2 conjugation, and therefore have little or no involvement with the CYP system, have minimal interaction potential.

The CYP3A4 enzyme is the primary metabolizer of fentanyl and oxycodone, although normally a small portion of oxycodone undergoes CYP2D6 metabolism to oxymorphone.

Tramadol undergoes both CYP3A4- and CYP2D6-mediated metabolism.

Methadone is primarily metabolized by CYP3A4 and CYP2B6; CYP2C8, CYP2C19, CYP2D6, and CYP2C9 also contribute in varying degrees to its metabolism.

The complex interplay of methadone with the CYP system, involving as many as 6 different enzymes, is accompanied by considerable interaction potential.

Smith H. S. (2009). Opioid metabolism. Mayo Clinic proceedings, 84(7), 613–624. doi:10.1016/S0025-6196(11)60750-7

Cytochromes P450 (henceforth P450s) constitute a superfamily of heme enzymes found from bacteria to humans

The most important property of all known P450s is their ability to bind and activate two atoms of oxygen. In most cases, it is the dioxygen molecule

The ability of all P450s to activate the Fe–O–O moiety(universal for all P450s) is determined by the mode by which the heme (here, heme b) is bound to apoprotein. The central atom of the heme macrocycle, i.e., the heme iron, is bound to the protein through the anionic, thiolate sulfur of a cysteine residue.

the P450 enzymes were according to recommendation of the International Union of Biochemistry, named as ‘heme-thiolate proteins’ to stress this fact. However, as this name was found to be misleading, because chloroperoxidases and NOS werefound to be heme-thiolate proteins as well, the name‘heme-thiolate protein’ for P450 enzymes has been completely abandoned.

The third common property (with the ability to activate

the O–O bond as the first, and with the thiolate bond to

the heme iron as the second characteristic property) of all

P450 enzymes is their similar overall structure and shape.

Anzenbacher, P., & Anzenbacherová, E. (2001). Cytochromes P450 and metabolism of xenobiotics. Cellular and Molecular Life Sciences, 58(5), 737–747. doi:10.1007/pl00000897

        1. Cytochrome P450 enzyme CYP3A4

Human drug-metabolizing P450 enzymes are present,

throughout the body. CYP3A4 is the most important P450 enzyme for drug metabolism in humans. This is not only because of its amount in the liver (which may be increased by induction to more than 60%) but mainly because it participates in the metabolism of the majority of drugs with known metabolic pathways.

CYP3A4 activity, as estimated from the levels of a known endogenous metabolic product, 6b-hydroxycortisol, relative to levels of cortisol as the substrate, changes during the day, with a maximum in the evening between 17 and 21 hours.

The spectrum of drugs known to be metabolized at least partly by CYP3A4 is extremely broad ranging from taxol to sildenafil (Viagra) [33]. This fact leads to the undesired possibility of drug interactions which may lead to extremely elevated or diminished levels of one of the interacting drugs.

For example, simultaneous administration of a drug which blocks CYP3A4 (e.g., an azole antifungal) together with another drug with a relatively narrow therapeutic window (i.e., a drug which should be given in a relatively narrow range of dosages to avoid health risks) can lead to levels of the second drug approaching or exceeding the limits of safety. This was apparently the case for azole antifungals with terfenadine or cisapride. In both cases, increased levels of terfenadine or cisapride were documented to cause life-threatening heart arrythmias.

Among drugs which are taken as ‘classical’ CYP3A4 substrates with great interacting potential are calcium channel blockers of dihydropyridine structure (e.g., nifedipine), most of the macrolide antibiotics (e.g., erythromycin), and azole antifungals (e.g., clotrimazole, ketoconazole). The latter group, azole antifungals, are the most potent inhibitors of CYP3A activity with apparent inhibition constants in the micromolar range.

Table 3. Drugs which are known to be substrates of (or to interact with) the CYP3A4 enzyme.

Acetaminophen (paracetamol)























Cyclosporin A , G






















Hypericum extract


























Paclitaxel (Taxol)







Retinoic acid (Tretinoin)


























Warfarin (R-)




Interactions are not only observed with drugs: constituents of the diet may also take part in drug interactions.

An example of this effect is the well-known inhibitory action of grapefruit juice, which was discovered rather serendipitously [39]. In this case, the in vivo effect can be quite dramatic with a single glass of grapefruit juice resulting in fivefold increases in the values of the main pharmacokinetic parameters such as the Cmax (maximal level) and AUC (area under pharmacokinetic curve) for dihydropyridine beta-blocking agents (e.g., nifedipine). The molecular basis is apparently the inhibition of CYP3A4 (possibly the intestinal one) by flavonoids present in grapefruit juice

Anzenbacher, P., & Anzenbacherová, E. (2001). Cytochromes P450 and metabolism of xenobiotics. Cellular and Molecular Life Sciences, 58(5), 737–747. doi:10.1007/pl00000897

        1. Cytochrome P450 enzyme CYP2D6

CYP2D6 is possibly the most popular cytochrome P450 among physicians and other health professionals, because of its genetic polymorphism (causing the presence of three main phenotypes of oxidative metabolism of drug substrates of this enzyme).

These three phenotypes are classified as the slow metabolizers (with defective CYP2D6 alleles), the extensive (or rapid) metabolizers (with the wild-type allele or with alleles having nucleotide changes not causing altered activity of CYP2D6), and the ultra rapid ones with multiple genes for the functional CYP2D6 enzyme

Extensive studies have shown that in the Caucasian population, there are about 7% defective CYP2D6 genes, whereas in the Asian population the frequence of defective alleles is almost one-half.

The impact of decreased activity of CYP2D6 on drug treatment may be extremely important, because elevated levels of tricyclic antidepressants may lead to cardiotoxic effects, in the case of inhibitors of selective reuptake of serotonin it may lead to nausea, and with antiarrythmics, undesired and life threatening arrythmias may develop.

The list of CYP2D6 substrates (table 4) is rather representative; principal substrates are b-adrenoreceptor blockers and tricyclic antidepressants.

Table 4. Substrates (drugs) of the CYP2D6 enzyme.















































Anzenbacher, P., & Anzenbacherová, E. (2001). Cytochromes P450 and metabolism of xenobiotics. Cellular and Molecular Life Sciences, 58(5), 737–747. doi:10.1007/pl00000897

Although CYP2D6-metabolized drugs have lower interaction potential than those metabolized by CYP3A4, genetic factors influencing the activity of this enzyme can introduce substantial variability into the metabolism of hydrocodone, codeine, and to a lesser extent oxycodone. An estimated 5% to 10% of white people possess allelic variants of the CYP2D6 gene that are associated with reduced clearance of drugs metabolized by this isoenzyme,29-31 and between 1% and 7% of white people carry CYP2D6 allelic variants associated with rapid metabolism.32,33 The prevalence of poor metabolizers is lower in Asian populations (≤1%)34 and highly variable in African populations (0%-34%).35-39 The prevalence of rapid metabolizers of opioids has not been reported in Asian populations; estimates in African populations are high but variable (9%-30%).

The clinical effects of CYP2D6 allelic variants can be seen with codeine administration. Patients who are poor opioid metabolizers experience reduced efficacy with codeine because they have a limited ability to metabolize codeine into the active molecule, morphine. In contrast, patients who are rapid opioid metabolizers may experience increased opioid effects with a usual dose of codeine because their rapid metabolism generates a higher concentration of morphine.40 Allelic variants altering CYP2D6-mediated metabolism can be associated with reduced efficacy of hydrocodone or increased toxicity of codeine, each of which relies entirely on the CYP2D6 enzyme for phase 1 metabolism.

Codeine is a prodrug that exerts its analgesic effects after metabolism to morphine. Patients who are CYP2D6 poor or rapid metabolizers do not respond well to codeine. Codeine toxicity has been reported in CYP2D6 poor metabolizers who are unable to form the morphine metabolite42 and in rapid metabolizers who form too much morphine.61,62 In fact, a recent study found that adverse effects of codeine are present irrespective of morphine concentrations in both poor and rapid metabolizers,63 suggesting that a substantial proportion of patients with CYP2D6 allelic variants predisposing to poor or rapid codeine metabolism will experience the adverse effects of codeine without benefitting from any of its analgesic effects. Codeine is also metabolized by an unknown mechanism to produce hydrocodone in quantities reaching up to 11% of the codeine concentration found in urinalysis.

Smith H. S. (2009). Opioid metabolism. Mayo Clinic proceedings, 84(7), 613–624. doi:10.1016/S0025-6196(11)60750-7

      1. Phase 2 Detoxification

Morphine, oxymorphone, and hydromorphone are each metabolized by phase 2 glucuronidation and therefore have little potential for metabolically based drug interactions.

Oxymorphone, for example, has no known pharmacokinetic drug-drug interactions, and morphine has few.

Of course, pharmacodynamic drug-drug interactions are possible with all opioids, such as additive interactions with benzodiazepines, antihistamines, or alcohol, and antagonistic interactions with naltrexone or naloxone.

However, the enzymes responsible for glucuronidation reactions may also be subject to a variety of factors that may alter opioid metabolism. The most important UGT enzyme involved in the metabolism of opioids that undergo glucuronidation (eg, morphine, hydromorphone, oxymorphone) is UGT2B7. Research suggests that UGT2B7-mediated opioid metabolism may be altered by interactions with other drugs that are either substrates or inhibitors of this enzyme.

Preliminary data indicate that UGT2B7 metabolism of morphine may be potentiated by CYP3A4, although the clinical relevance of this finding is unknown.

The activity of UGT2B7 shows significant between-patient variability, and several authors have identified allelic variants of the gene encoding this enzyme.

Although the functional importance of these allelic variants with respect to glucuronidation of opioids is unknown, at least 2 allelic variants (the UGT2B7-840G and -79 alleles) have been linked to substantial reduction of morphine glucuronidation, with resulting accumulation of morphine and reduction in metabolite formation.

Smith H. S. (2009). Opioid metabolism. Mayo Clinic proceedings, 84(7), 613–624. doi:10.1016/S0025-6196(11)60750-7

        1. UDP-Glucuronosyltransferase-2B7 UGT2B7

Uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT) is a cytosolic glycosyltransferase (EC that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is a glucuronidation reaction.

Glucuronosyltransferases are responsible for the process of glucuronidation, a major part of phase II metabolism.

The reaction catalyzed by the UGT enzyme involves the addition of a glucuronic acid moiety to xenobiotics and is the an important pathway for the human body’s elimination of the most frequently prescribed drugs. It is also the major pathway for foreign chemical (dietary, environmental, pharmaceutical) removal for most drugs, dietary substances, toxins and endogenous substances.

The glucuronidation reaction consists of the transfer of the glucuronosyl group from uridine 5′-diphospho-glucuronic acid (UDPGA) to substrate molecules that contain oxygen, nitrogen, sulfur or carboxyl functional groups.

The resulting glucuronide is more polar (e.g. hydrophilic) and more easily excreted than the substrate molecule. The product solubility in blood is increased allowing it to be eliminated from the body by the kidneys.

    1. Enkephalins in the Brain

The enkephalin system exists solely in the brain. Many of the criteria for the classification of “neurotransmitter” have been met by the enkephalins. They are located at nerve terminals, are readily degraded, and can be released by electrical stimulation, or by high concentrations of potassium ions, as was demonstrated in brain slices.


Enkephalin-like peptides in plasma are probably derived from the adrenal medulla since brain pentapeptides have a very short half-life in plasma. Enkephalins in CSF, on the other hand, are probably released from the central nervous system.


Met- and Leu-enkephalin are found in short interneurons and are released from the nerve terminals when the neuron is stimulated, thus acting like neurotransmitters .



Enkephalins may share a common precursor with growth hormone. It has been reported that the adrenal gland contains a precursor polypeptide for enkephalins.



As opposed to these findings, destruction of striatal neurons with kainic acid decreases enkephalin content by 50%.



      1. Enkephalins and Dopa pathways

Results of a number of studies have suggested a close relationship between enkephalinergic and dopaminergic neurons, and also a possible role of the endogenous opiate peptides in the pathogenesis of some mental disorders.


      1. Antipsychotics Raise Enkephalin Levels

Chronic administration of cataleptogenic antipsychotic drugs, haloperidol, chlorpromazine, and pimozide, but not of the non-cataleptogenic antipsychotic, clozapine, has been reported to produce in rats a long-lasting increase of striatal Met-enkephalin concentration.

Long-term administration of haloperidol increased the content of Met-enkephalin in the caudate nucleus, globus pallidus, nucleus accumbens, medial and lateral preoptic nuclei, and interpeduncular nucleus), but not in the hypothalamus, medulla oblongata, and septum.

It was suggested that the blockade of dopaminergic transmission by haloperidol could be the cause of an increase of synthesis and accumulation of striatal enkephalins.

Neuroleptic dopamine receptor blockers may increase the enkephalin content in the CNS by inhibiting the enkephalin-hydrolyzing system.

Inhibition of enkephalin degradation by human brain cortex extract was apparent with concentrations of neuroleptics that may be present in the CNS, especially after long-term clinical treatment.

The inhibition of enkephalin-hydrolyzing activity in cerebrocortical and cerebellar extracts by thioridazine, chlorpromazine, pimozide, fluphenazine, haloperidol, and promazine was concentration dependent, with IC50s of about 50, 80, 100, 120, 200, and 250 microM, respectively.

Neuroleptics had comparable inhibiting effects on enkephalin degradation in extracts of rat brain tissues such as the cortex, cerebellum, and caudate nucleus.

Kinetic studies on enkephalin-hydrolyzing activity in human brain cortex extracts indicated noncompetitive and competitive inhibition by thioridazine and chlorpromazine, respectively.

These data suggest that an accumulation and increased availability of enkephalins in CNS, resulting at least partly from inhibition of degradation that may occur during antipsychotic treatment.

The present data suggest that direct interference with the degradation of enkephalins in the CNS may be part of the complex mechanism of action of various antipsychotic drugs.


There are three chemical families of neuroleptic drugs: the phenothiazines, the thioxanthenes, and the butyrophenones. Most of the drugs have antipsychotic activity and selectively antagonize dopamine. The extrapyramidal effects of some neuroleptics are related to the low affinity for the muscarinic acetylcholine receptor, with haloperidol having the lowest and clozapine the highest affinity.



      1. Tricyclic Antidepressants Raise Enkephalin Levels

The tricyclic antidepressants, imipramine and desipramine, but not doxepin showed similar concentration-dependent inhibitions (with IC50s of about 250 microM) of the hydrolysis of Met-enkephalin by human brain cortical extracts (Table 3).


Tricyclic antidepressants (TCAs) such as imipramine and amitriptyline are agents that produce mood elevation with side effects of sedation and hypotension. These drugs bind at high affinity to histamine receptors, both H1 and H2 receptors.

With lower affinity they also bind to muscarinic and alpha-adrenergic receptors. Although the levels of the inhibitory neurotransmitter, histamine, in the central nervous system are highest in the hypothalamus, the lower levels in the hippocampus and striatum seem to be more intimately involved in neurotransmission. In these brain areas, histamine activates adenylate cyclase via H2 receptors.

The activation of the stimulation by histamine of adenylate cyclase is antagonized by TCAs. Stimulation of the H1 histamine receptor increases cGMP formation, another effect blocked by TCAs. The TCAs are potent antihistaminics, more potent than most drugs used clinically for this purpose.

These drugs also block the reuptake of catecholamines and serotonin with the highest uptake inhibition in the hypothalamus. A minor adverse effect of TCAs, the induction of hallucinations, is probably related to the fact that d-LSD is a very potent H2-receptor blocker.

One of the earliest observed responses to the administration of morphine is the release of histamine in the periphery, a phenomenon that could account for the hypotension, vomiting, and tachypnea produced by opioids.

In the hypothalamus, chronic morphine treatment lowers histamine levels, and withdrawal from morphine lowers them still further.

Hippocampal histamine neurons are inhibitory and decrease firing in hippocampal neurons. Opioids have a similar effect in the hippocampus although the opioid effect is mediated by a GABA inhibitory system.



      1. Diazepam Increases Enkephalins in Hypothalamus

Acute treatment of rats with the tranquilizer diazepam has been shown to induce regional changes in brain enkephalin levels, namely a dose-dependent and rapid increase in the hypothalamus, a decrease in the striatum, and no changes in some other areas.

In contrast, chronic treatment with diazepam resulted in an increase in the striatal Met-enkephalin content, with no changes in the hypothalamus and other brain areas. It was suggested that benzodiazepines may affect endogenous opiates in the CNS by various mechanisms.

Diazepam showed a dose-dependent inhibitory effect (with an IC50 of about 500 microM) on the degradation of Met-enkephalin by human brain cortical extracts.


The benzodiazepines are a class of minor tranquilizers that are useful clinically as muscle relaxants, anticonvulsants, and hypnotics, as well as anxiolytics. Electrophysiological studies suggest that these drugs have a specific interaction with GABA neurons.

The benzodiazepine receptors are characterized by their widespread distribution related to the distribution of GABA synapses, in contrast to the heterogeneous distribution of opioid receptors. The level of cyclic GMP (cGMP) varies inversely with the levels of GABA in GABAergic tissue

Thus, GABA and benzodiazepines depress cGMP levels in the striatum, and morphine and beta-endorphin increase cGMP levels in the same tissue.

In the cerebellum, both benzodiazepines and GABA decrease the levels of cGMP in the Purkinje cell. Morphine administration also decreases the cGMP level, but by an indirect mechanism related to dopamine control of the excitatory input to the cerebellum.

There is, however, an interaction between benzodiazepines and endogenous opioids. In rats, diazepam treatment results in a rapid decrease in enkephalin levels in the striatum but not in midbrain, medulla, or other areas.



      1. Aromatic Neurotransmitters Inhibit Enkephalin Degradation

Some neurotransmitters, norepinephrine, serotonin, and especially dopamine, produce a marked concentration-dependent inhibition of enkephalin degradation. This may indicate an essential and direct regulatory role of these neurotransmitters in the metabolism of enkephalin.

Psychoactive agents and enkephalin degradation



    1. Endorphins in the Pituitary

The endorphin system is distributed largely in the pituitary and to some extent in the brain.

It has been suggested that one of the possible physiological roles of the endorphins may lie in the regulation of the anterior pituitary hormones.

The involvement of the endorphin-opiate receptor system in a variety of physiological, behavioral, and pathological states has been the subject of many reports. These studies have frequently involved demonstrating that a given phenomenon is affected by specific opiate antagonist or endorphin administration.


We have not as yet found a brain structure devoid of immunoreactive beta-Endorphin. Regional differences in beta-Endorphin concentrations vary a hundredfold in the following sequence from highest to lowest values: hypothalamus > nucleus accumbens > amygdala > septal nuclei > midbrain > hindbrain > pyriform and entorhinal cortex > hippocampus > cerebellum > neostriatum > neocortex.

These data indicate that even excluding the hypothalamus, limbic system structures contain concentrations of immunoreactive beta-endorphin 5- to 10-fold greater than those elsewhere in the brain.

Hypophysectomy causes a dramatic decrease in the brain concentration of beta-Endorphin. A 5- to 10-fold reduction in brain Beta-Endorphin concentration was observed in hypophysectomized rats.

The 90% decrease in beta-endorphin concentration observed in the brain after hypophysectomy suggests the pituitary as a major source of brain beta-Endorphin or that pituitary hormones may secondarily influence endorphin synthesis by the brain.



Beta-Endorphin is found in high concentrations in the pituitary gland and is released into the bloodstream by agents such as stress and thus acts like a neurohormone. Beta-Endorphin is also found in the hypothalamus in neurons with long axons extending to almost every other brain area.



The levels of beta-Endorphin in the plasma presumably reflect its release from the pituitary gland, whereas the levels of Beta-endorphin in cerebrospinal fluid (CSF) more closely reflect the release of the opioid from brain.


The glycoprotein pro-opiocortin is the parent substance for both adrenocorticotropic hormone (ACTH) and beta-Endorphin.

Hormones from the anterior and posterior pituitary lobes are essential for homeostasis of the organism. In addition to the peripheral effects, these hormones exhibit, as well as their fragments, direct influences on brain functions. This central action has become apparent from their influence on animal behaviour. These behaviourally active peptides are termed neuropeptides.

Endorphins can exert an influence on various kinds of behaviour.


Opiate Receptors and Opiate

Antagonists in Psychiatric and

Related Research

A Review



Beta-Endorphin has significant CNS actions and it produces EEG changes in humans. Animal studies show that iv Beta-Endorphin enters the brain and increases CSF levels of beta-endorphin


      1. Endorphin Excess Theory

According to one view, the increased levels of endorphins or endorphin fractions observed in the CSF and other body fluids of schizophrenic subjects suggested that excess production of these neuropeptides may be involved in the development of psychosis.

chapter 1

Endorphin Excess

A great deal of research effort was directed toward the proposition of endorphin excess in psychosis. Part of the supporting evidence for this hypothesis was obtained from an animal model of human catatonia, i.e., beta-endorphin-induced muscular rigidity in the rat. This model has been used in experimental procedures for the production of catatonia by intracerebroventricular injection of Beta-endorphin.

The manifestation of the syndrome is reversible by naloxone, an opiate antagonist. An apparent similarity between the Beta-endorphin-induced muscular rigidity in rats and the catatonia seen in schizophrenic subjects led to the postulation of the “beta-endorphin excess” theory of schizophrenia.

Elevated levels or overactivity of those opioid neuropeptides are thought to be involved in the pathogenesis of schizophrenia. It should be emphasized that because of rapid degradation of most of the opioid neuropeptides in a physiological state, such a biochemical abnormality may last only for a short duration.


The first direct evidence for this hypothesis was obtained from a small group of schizophrenic patients, who were found to have increased concentrations of two endorphin fractions in the cerebrospinal fluid (CSF) in a drug-free state.

This finding was supported by later studies; furthermore, patients with manic-depressive disorders and puerperal psychosis have been found to have increased levels of endorphins in CSF and plasma.

Indirect support for the hypothesis comes from studies with the opiate antagonist naloxone. A decrement especially of auditory hallucinations has been reported in selected patients, but others have failed to replicate these results. A relationship between endorphins and mental disturbances has also been suggested by several investigators.



Of the 53 schizophrenic patients studied 45% had elevated fraction I and 62% fraction II endorphin levels in at least one CSF sample, with or without medication when compared to healthy volunteers. When either fraction I or fraction II was considered, pathological increment was seen for 72% of the whole group of schizophrenics.


Many schizophrenic patients have elevated CSF endorphin levels



One limitation in the interpretation of the results is the fact that we do not know the chemical composition or the anatomical sites of synthesis and action of fraction I and II endorphins.

A potentially important finding with diagnostic implications is the fact that patients classified as hebephrenic more often had increased levels of fraction I.

This subtype is characterized by a symptom-rich clinical picture initially, an early onset of the disease often with a poor prognosis, and it would therefore not be surprising to find a clear biological basis for schizophrenia within this subgroup.

The existence of peptides with opioid activity has been demonstrated by use of radioimmunoassay in CSF from healthy humans as well as opioid materials that resemble enkephalin.

A few studies have also been carried out in schizophrenic patients. A CSF component designated as enkephalin-like material was more rapidly inactivated by chronic schizophrenics than by controls, suggesting an altered enzymatic activity in CSF in the disease group.

These results could not be replicated by Burbach et al. (1979), who stated that altered levels of endorphins in CSF of schizophrenic patients reflect changes in brain metabolism and release.

In a study by Domschke et al. (1979), it was reported that five patients with acute schizophrenia had a 10-fold increase of the beta-endorphin level in CSF, whereas those with a chronic course had lower concentrations than controls.

Two fractions (I and II) of lumbar CSF endorphins were analyzed in 53 schizophrenic patients and 19 healthy controls with no history or drug-free period. Hitherto, we have studied a nonselected sample of patients with the diagnosis of schizophrenia and there are reasons to believe that this diagnostic group is heterogeneous in a biological sense. The next step of investigation seems to warrant a somewhat different strategy.



Hebephrenic patients were found to have increased fraction I levels more often than the undifferentiated group of schizophrenia, whereas no difference between the two subgroups was seen for fraction II.

The CSF endorphin concentrations were not found to correlate with the severity of the schizophrenic symptoms, the duration of the disease, or the length of the drug-free period.

Of the 53 patients studied, 72% had pathologically elevated endorphin levels in at least one CSF sample. It was also found that the highly elevated levels of fraction I seen in some patients when they were in a state of intense psychosis, decreased after treatment with neuroleptics. No clear-cut pattern was seen for fraction II as a result of drug treatment.

The present data lend support to the view that schizophrenia is sometimes connected with a disturbance of CNS endorphins.

The schizophrenic patients tended to be worse on the overall subacute rating after beta-endorphin as compared to placebo (p < 0.01). When the responses of the two patient groups were compared to one another, a significantly worse response to beta-endorphin was found for the schizophrenic compared to the depressed patients (p < 0.01 by t test for independent samples).


I.V. Beta-endorphin produces behavioural effects in psychiatric patients over a 2- to 4-hr period. There was a tendency toward greater worsening after beta-endorphin than after placebo over the 5 days after infusion, consistent with the subacute trend on infusion days.

The typical schizophrenic subject developed more psychotic distortion and became less communicative, and more socially withdrawn after Beta-endorphin infusion.

Subject No. 14, This young male, chronic schizophrenic had led a vagabond life between frequent psychiatric hospitalizations. His thoughts were bizarre, loose, and disorganized, although not overtly paranoid, and he could easily engage in conversation with others. He had constant auditory hallucinations of voices that he would react to and freely discuss with his therapist. Although obviously ill, he was well liked by staff and other patients. After his first infusion (placebo), he appeared to be slightly more talkative during the evening, discussing the procedure with the other patients. No other changes were evident over the ensuing week. Within 3 hr after the second infusion (10 mg Beta-endorphin), he became mute and withdrew to his bed, looking suspiciously at this therapist, whom he usually liked. By the following day, he was hallucinating more and had great difficulty communicating with others. He was given haloperidol after another day and responded over a week, finally reaching the moderately functional state he had achieved in past hospitalizations.


Depressed patients improved subacutely following Beta-Endorphin, while schizophrenic patients tended to worsen. This differential response suggests that endorphin systems may have different roles in the two illnesses. Other possible explanations for this differential response include artifact because of small sample size and group differences in medication history (75% of schizophrenic patients had recently received neuroleptic, while only 10% of depressed patients had).

In addition to studies investigating the role of exogenous opioids in the regulation of affect, the role of opioids in the regulation of schizophrenic symptoms has been researched.

With respect to our studies of the role of endogenous opioids in schizophrenia, we have based our studies on observations that

(1) naloxone plus an antipsychotic drug exerts synergistic effects on behavioural variables in pigeons;

(2) that naloxone has been reported to exert antihallucinatory effects in schizophrenics

(3) that beta-Endorphin, and a variety of other opiates and opioids, causes a naloxone-reversible catatonic-like syndrome in rats;

(4) that endogenous opioidlike compounds are elevated in the CSF of manics and schizophrenics;

(5) that beta-endorphin has been reported to alleviate schizophrenic symptoms; and

(6) that beta-Endorphin in relatively high doses causes stereotyped rat behaviour similar to that caused by amphetamine, considered an animal model of psychosis.

Naloxone and methadone have been used as exploratory tools to investigate the role of endogenous opioids in the regulation of affective and schizophrenic symptoms. Results have demonstrated a possible antimanic effect of naloxone in a subgroup of manic patients.

        1. Naloxone in Schizophrenia

The first evidence that linked endorphins to psychiatric illnesses was the observation by Terenius in 1976 of elevated cerebrospinal fluid (CSF) levels of endorphins in some chronic psychotic patients, which led these investigators to suggest that increases in endorphin levels were perhaps implicated in the physiological substrates underlying the psychoses.

These investigators subsequently reported a dramatic reduction or cessation of hallucinations following administration of naloxone, which was compatible with their contention. Later studies showed elevated CSF levels of uncharacterized endorphin-like material in acutely ill schizophrenics.


Schizophrenia has been extensively studied with opiate antagonists.

Several studies have reported a decrease in some symptoms (especially hallucinations) after treatment with naloxone, implicating increased endorphin activity in this disorder. However, many other studies have reported no change. In general, most studies found a positive effect using an open design, while the negative studies were double-blind. It remains possible that positive effects were missed in some studies because of the particular doses and frequency of administration used.



        1. Endorphins in Schizophrenia

Several studies indicate enhanced levels of endorphins in biological fluids of schizophrenic subjects. Several hypotheses have been proposed to explain these elevated levels.

Enhanced biosynthesis of β-lipotropin (a precursor of endorphins) and its accelerated breakdown to endorphin peptides could result in a surge in the release of beta-endorphin or related psychotogenic peptides, thereby promptly flooding the brain areas and concomitantly elevating CSF levels.


Kline et al first published the work in 1977 with human patients and suggested Beta-endorphin administration might produce beneficial changes in depressed and schizophrenic patients. Kline and Lehmann extended their work in 1978 to patients with problems other than depression or schizophrenia.

Verhoeven et al. administered DTyE to schizophrenics and found improvement in all six patients, although it was reported to be brief in three patients. Verhoeven et al. (1979) subsequently reported additional work with the same analog.

In the first study, six patients were removed from all neuroleptic medication and administered 1 mg of DTyE daily, intramuscularly, for 7 days. In the second study, which used eight patients in a double-blind procedure, the same dose of DTyE was administered for 8 days in conjunction with conventional neuroleptic medication.

The results of both studies suggest some improvement of symptoms. The second study was more effective, reporting that by day the psychotic symptoms had virtually disappeared.

Krebs and Roubicek (1979) administered FK 33-824, an analgesically potent analog of Met-enkephalin, intramuscularly and found a temporary improvement in the symptoms of four of six psychotic patients. Nedopil and Ruther (1979) used the same analog and found improvement in five of nine patients, although three dropped out early in the study.

Particularly in schizophrenia and manic-depressive psychosis there is some evidence for the clinical importance of opioid-Prostaglandin E1 (PGE1) interactions. Evidence suggests that depression and alcoholism may also be promising fields for investigation.


In high doses (> 50 microgram centrally), beta-endorphin induces motor immobility and muscle rigidity. This akinetic state has been equated by some with schizophrenic catatonia.


A controversy that developed over the influence that schizophrenia has on endorphin levels has been settled by the discovery that patients treated chronically with antipsychotic drugs have plasma endorphin levels 10-fold higher than control subjects.

Two opposite theories on the role of endorphins in schizophrenia have evolved. In one theory, endorphins are superabundant in the central nervous system of schizophrenics, requiring a narcotic antagonist to block some of the excess opioid activity and normalize the patient.

In the other theory, endorphin levels in the central nervous system and pituitary gland have decreased or have become abnormal and nonfunctional in some way such that exogenous opioids are needed to maintain emotional balance. Both theories have been tested clinically.


In 1975 Terenius and Wahlstrom isolated two endorphin fractions (I and II; opiate-like material) from human CSF. Neither of these fractions has yet been identified as any of the known endorphins. The concentrations of these fractions were determined in 13 patients with schizophrenic psychoses and 7 with manic-depressive psychoses.

Of the 13 schizophrenic patients, an increased fraction I or II endorphin concentration was found in 9 and 4, respectively. In all of these patients, fraction I and in 2 of the 4 patients, fraction II was reduced to normal levels by neuroleptic medication with accompanying reduction in psychotic symptoms. In the 7 manic patients, an increased fraction I endorphin concentration was found during the manic phase. A correlation between fraction II endorphin and clinical symptoms was not clearly demonstrable in these patients.

Beta-Endorphin concentration in CSF was found to be markedly increased in 5 patients with acute schizophrenic psychoses, while in 7 chronic psychotic patients it was normal or slightly decreased (Domschke et al., 1979).

In 1979 Emrich et al reported that in 15 patients suffering from both acute and chronic schizophrenia a normal concentration of beta-Endorphin in plasma and CSF was found. A slightly decreased concentration of an enkephalin-like compound in CSF was reported in 19 patients with chronic schizophrenia.

Burbach et al. (1979) found no significant decrease in degradation of beta-endorphin and Met-enkephalin in CSF of schizophrenics compared to that of controls.

Loeber et al. (1979) have demonstrated the presence of a- and y-endorphin in human CSF. Whether their concentrations show changes in psychiatric patients has not yet been well established.



In an open study without a clearly defined protocol, a total dose of 9 mg beta-endorphin (distributed over 4 days) was injected intravenously in five patients with schizophrenic psychoses and two with depressions (unipolar and bipolar, respectively), (Kline et al , 1977; Kline and Lehmann, 1978).

A few minutes after the injection, an activating, anxiolytic, and antidepressant effect was observed and this persisted for 2-3 hr; a degree of drowsiness developed 2-4 hr post-injection; about 12 hr post-injection, a further therapeutic effect was observed that was characterized by reduction of the depressive or psychotic symptoms, lasting from 1 to 10 days. However, recent attempts to replicate these findings have failed.



The hypothesis of a pathological significance of endorphins in various types of psychoses is based on the following two observations: First, the euphorogenic actions of opiates and endorphins (Kline et al., 1977) in normal subjects and the antidepressive action of the synthetic analog of Met-enkephalin, FK 33-824, in psychotic patients (Nedopil and Ruther, 1979), which led to speculation that endogenous opioids may be responsible for mood changes in affective psychoses (Terenius et al., 1977).

Second, certain partial opiate agonists, such as cyclazocine and nalorphine, induce hallucinations and derealization experiences in healthy volunteers (Jasinski et al., 1967) supports the contention that productive symptoms (e.g., hallucinations and delusions) in schizophrenic patients may reflect an abnormality in the functioning of endogenous opioid systems.

Terenius et al., (1976) and Lindstrom et al. (1978) discovered, by use of a radio-receptor assay, that increased levels of endorphins are present in the cerebrospinal fluid (CSF) of schizophrenic patients.

An additional finding, which suggests the undertaking of opioid investigations in psychotic patients, is derived from chemical analyses of the dialyzates of schizophrenic patients.

Patients were hemodialyzed by Wagemaker and Cade (1977), who claim that this method is effective in the treatment of patients suffering from chronic schizophrenia. Palmour et al. (1979) estimated exceptionally high levels of [Leu5]-beta-endorphin in the dialysate (and in the plasma) of these patients and speculated that the elimination of this abnormal opioid from blood might be responsible for the possible therapeutic effects of hemodialysis in these schizophrenic patients.




In the CSF study, lumbar taps were performed between 0900 and 1100 hr. Patients with the following types of diagnoses were included in the study:

a. Schizophrenia (acute and chronic cases).

b. Encephalitis/meningitis.

c. Neurological disorders (epileptic seizures, cerebral atrophy, multiple sclerosis, etc.)

A control group consisted of patients punctured owing to a suspicion of meningitis/encephalitis but who turned out to possess normal CSF. All patients with schizophrenia (group a), with the exception of two acute cases, were treated with neuroleptic drugs.



Investigations as to a possible abnormality in the levels of beta-endorphin immunoreactivity in the plasma of schizophrenic patients as compared to those suffering from other neuropsychiatric disorders have been reported (Hollt et al., 1978b; Emrich et al., 1979).

No apparent differences were detectable between patients exhibiting different types of neuroses, mania, endogenous depression, organic types of psychoses, and schizophrenia.



One of the central questions raised by the endorphin hypothesis of schizophrenia concerns the possible existence of abnormal opiate substances in CSF and/or plasma of schizophrenic patients.

There is a tendency toward an increase in levels of beta-endorphin-like immunoreactivity in the group of patients with schizophrenia. Therefore, the existence of a subgroup of patients displaying an abnormality in their beta-endorphin and related peptides cannot be excluded.

The findings of a tendency toward lower values of Beta-endorphin-like immunoreactivity in a group of patients possessing mixed neurological disorders (epileptic seizures, cerebral atrophy, multiple sclerosis, etc.) may be of interest insofar as this is in a direction opposite to that exhibited by schizophrenic patients.

This effect, although statistically significant, is only of small magnitude and is possibly attributable to the fact that patients with degenerative disorders of the CNS (e.g., cerebral atrophy) were included in this group.

The lack of any dramatic change in levels of Beta-endorphin in the CSF of schizophrenic patients is not necessarily in contradiction to the findings of Terenius et al. (1976).

It is conceivable that, in the CSF, elevated values of opioid peptides other than Beta-endorphin are occurrent. A putative canditate for such substance is the recently discovered extremely potent opioid peptide dynorphin (Goldstein et al., 1979).

The molecular weight of this peptide (about 1700) coincides well with that estimated for the fraction I peptide of Terenius et al. (1976). In fact, Wahlstrom and Terenius have recently determined that fraction I consists of at least three different components, one of which cross-reacts with dynorphin antibodies (Wahlstrom, personal communication).

The relative distribution of the immunoreactive components observed (precursor, Beta-LPH, Beta-endorphin) apparently reveals no obvious differences between schizophrenic patients and normal subjects. An elevation in levels of Beta-endorphin could have been obscured by a depression in the amounts of Beta-LPH or other immunoreactive components present.

A further question pertinent to a consideration of recent endorphin hypotheses of schizophrenia relates to the findings of Palmour et al. (1979) of elevated levels of [Leu]-beta-endorphin in the plasma and dialysate of schizophrenic patients. According to the present investigations (see Emrich et al., 1979), schizophrenics appear to have no dramatically increased levels of [Leu5]-beta-endorphin in their plasma, since this peptide cross-reacts in the RIA. This finding is in agreement with the observations of Lewis et al. (1979) and Ross et al. (1979).



There is a small tendency toward higher values in schizophrenics. In a group of patients displaying mixed neurological disorders a tendency toward lower values was observed. beta-Endorphin-like immunoreactivity was measured in the plasma of three schizophrenic patients both before and after hemoperfusion. As compared to normal subjects, levels of beta-endorphin-like immunoreactivity were not greatly elevated in the schizophrenic patients prior to hemoperfusion. Instead of the anticipated decrease in levels, a consistent rise in plasma levels of immunoreactive beta-endorphin was detected upon hemoperfusion. Levels of beta-endorphin-like immunoreactivity in the plasma of two heroin addicts revealed a depression as compared to controls, while an increase in levels occurred during the first days of withdrawal.

CSF levels of beta-endorphin or uncharacterized endorphins have been reported to be elevated in acute (Domschke et al., 1979) and drug-free schizophrenics (Lindstrom et al., 1978). Other investigators have found levels in acute (Emrich et al., 1979a) and chronic schizophrenics (Domschke et al., 1979; Emrich et al., 1979a; Hollt et al., 1978) to be different from controls. Initial interest in elevated levels of a putative

One single-blind study has reported symptomatic improvement lasting hours to days in two of four male outpatient chronic schizophrenics given synthetic human beta-endorphin (1.5-9 mg by i.v. bolus) (Kline et al., 1977). Verhoeven et al. (1979) gave (des-Tyr1)-y-endorphin (1 mg i.m. daily) for 8 days to six schizophrenics in a placebo-controlled, doubleblind, crossover design and reported dramatic alleviation of symptoms after 24-48 hr. This response continued for 4-5 days after cessation of treatment. All but two of these patients were on concurrent neuroleptics.


        1. Hemodialysis in Schizophrenia

The observation of elevated levels of Beta-endorphin-like material in the cerebrospinal fluid of schizophrenic individuals (Terenius et al., 1976) added further support to the above hypothesis. The clinical improvement in schizophrenic patients following repeated hemodialysis (Wagemaker and Cade, 1977), which was proposed to be due to the removal of [Leu5]-Beta-endorphin (Palmour et al., 1979), suggests an endorphin excess in schizophrenia. However, the presence of [Leu5]-beta-endorphin in the hemofiltrates of schizophrenic and control patients could not be confirmed (Lewis et al., 1979). If elevated levels of opioid peptides are related to schizophrenia, one would expect naloxone to have an effect on psychiatric symptoms.


This is further substantiated by the finding by Ross et al. (1979) that no difference existed in plasma beta-endorphin-like immunoreactivity between 98 schizophrenic patients and 42 normal subjects, which was in direct contradiction to earlier reports of extremely high concentrations of [Leu5]-beta-endorphin in hemodialysates from schizophrenic patients (e.g., Wagemaker and Cade, 1977).




studies testing blood transfusion or exchange in schizophrenic patients (e.g., Kielholz, 1949), the first attempts to treat psychosis with hemodialysis (Feer et al., 1960) resulted in some improvement for three of five patients. For technical and other reasons, these attempts were abandoned. In 1977, Wagemaker and Cade initiated the current wave of interest in this field, by reporting striking remission of psychotic symptoms in an uncontrolled study of hemodialysis in 14 patients. Since that time, there have been uncontrolled, single-blind, and double-blind attempts to evaluate this finding (reviewed by Gentry et al., 1980). In brief, 27 of 46 patients showed some improvement in uncontrolled studies (Gentry et al., 1980; Pitts and Anilin, 1979; Drori et al., 1980); 10 of 56 long-term chronic schizophrenic patients showed improvement when dialyzed for kidney failure (Gentry et al., 1980); and in double-blind studies, at least 19 of 43 patients showed some improvement (Gentry et al., 1980; Malek-Ahmadi et al., 1980; Linkowsk et al., 1979; Fenton et al., 1980; van Kammen et al., 1980; Caudle, 1980).

Thus, hemodialysis is clearly not a treatment for all “schizophrenics.” Second, only those studies using membranes with a thickness of 13 micro m or less reported patient improvement. In an unconfirmed study, Pitts and Anilin (1979) reported progressively more rapid improvement if dialysis membranes of 11.5- and 10-micro m thickness, rather than 13-|micro m membranes, were used. Polyacrylonitrile membranes (Opolon et al., 1976) or cellulose acetate membranes (Lin-kowski et al., 1979) may offer even greater advantages.



Using either radioreceptor assay (RRA) or radioimmunoassay (RIA) to quantitate hemodialysate endorphin content, we have identified two different biological subpopulations among 12 of Wagemaker and Cade’s 14 original patients (Table 1). Radioreceptor assay reveals high levels of opioid material (range, 0.64-9.5 nM; mean, 4.5 nM) in organic extracts of first dialysate from seven patients. After 16 weeks of dialysis, dialysate opioid activity averaged 57 pM (range, less than 30 pM to 90 pM). The two highest terminal levels (80, 90 pM) were found in patients with moderate clinical response. Midpoint levels at 8 and 9 weeks of dialysis were 100 and 70 pM for two patients. Dialysate from a single patient at relapse, 16 weeks after the cessation of weekly dialysis, contained approximately 140 pM endorphin. We were unable to find high levels of opioid activity in hemodialysate of five patients, two of whom showed good improvement and three of whom did not improve significantly. An examination of hemofiltrate from renal patients (N = 5) failed to reveal evidence of high levels of opioid activity.

Radioimmunoassay shows rather different quantitative levels of Beta-endorphin-like material in the first group of seven patients


levels between 1st and 16th dialysates are statistically indistinguishable from those seen with radioreceptor assay. For the five patients with low initial levels, by contrast, radioimmunoassay identifies a two- to fourfold increase in endorphin immunoreactivity in the 16th dialysate; this small increase was not detected by radioreceptor assay. It is likely that this rise in endorphin immunoreactivity is an endocrine response to the stress of dialysis, as has been reported for ACTH and MSH (Gilkes et al., 1975; Rees, 1977; Bertagna et al., 1979).



We were bothered by the fact that hemodialysate levels of endorphin in these patients exceeded blood levels of endorphins reported in normal (Wardlaw and Frantz, 1979; Hollt et al., 1978) or schizophrenic (Ross et al., 1979) individuals. Indeed, we found higher dialysate levels of endorphin than would have been predicted by immunoassay of serum endorphin in three of these patients (Palmour, unpublished data). Moreover, endorphin immunoreactivity in 16th dialysate from high-endorphin patients, in 1st dialysate from low-endorphin patients, or in dialysate from renal patients is higher than would be predicted by normal serum levels (Table 3). Indeed, since each dialysis treatment uses 120 liters of fluid in a singlepass mode, the amount of endorphin found in a low-endorphin dialysate exceeds the total blood endorphin immunoreactivity by a factor of 72.



Thus, about 70% of total serum endorphin is bound to protein, while only 25-30% is free.



In the current studies, which are uncontrolled and which involve a very small patient sample, we have identified [Leu5]-beta-endorphin, alone or in combination with [Met5]-beta-endorphin, in hemodialysates from seven patients; in dialysate samples from several additional patients, some of whom showed clinical improvement, [Leu5]-beta-endorphin could not be identified. We now present evidence of two different subgroups of psychotic patients—one in whom initially high levels of endorphin immunoreactivity decline during dialysis, and another in whom initially normal levels of endorphin immunoreactivity increase 2- to 4-fold during dialysis.

We have now screened samples from more than 40 patients, some studied doubleblind. Both responsive and unresponsive patients were included. Those studies are still in progress and are not ready for final publication. In some patients, however, initially somewhat elevated levels of endorphin immunoreactivity (20-100 pM) decline 2- to 10-fold over 8-20 weeks of dialysis, while in others, initially low levels of endorphin immunoreactivity increase 2- to 3-fold. In no sample have we seen the very high levels of opioid material found in the seven patients reported here. Thus, it is possible that peptide extracted from the initial samples might be of bacterial or dietary origin. The recent demonstration that peptides with opioid activity can be generated by proteolysis of gluten (Klee et al., 1979) and the reports of decreased frequency of psychotic episodes in some patients on gluten-free diets (Singh and Ray, 1976) necessitate a testing of this hypothesis.



Ross et al. (1979) similarly have attempted to identify an elevated beta-endorphin level in the plasma of schizophrenic patients. In 92 males and 4 females, they found a range of 0.9 to 7.4 pM immunoassayable endorphin, after using an extraction technique that, in our hands, yields free endorphin, little bound endorphin, and electrophoretically detectable (micrograms) amounts of binding globulin. (The latter, in particular, interferes with accurate quantification of immunoreactive endorphin.) They conclude that at least 94% of all schizophrenic patients must have serum endorphin levels 7.4 pM or below.

Within this field, there is an unfortunate tendency to think in terms of averages, which has apparently precluded careful attention to the responsiveness of “outlying” patients to a particular therapeutic regimen or to the identification of biochemical markers in the rare or unusual patient. For example, Ross et al. (1979) report at least 15 schizophrenics and no normals with plasma beta-endorphin levels of 5 pM or higher, while Domschke et al. (1979) have recently recounted CSF levels of endorphin immunoreactivity in-acute psychotic patients that average 764 pM (10 times those of control subjects). Similar anecdotes can be furnished for virtually every marker for psychosis previously proposed, but not widely accepted.

Psychotic disorders would best be conceptualized as belonging to that category of disease termed multifactorial

well documented, the presence of a biological basis for psychotic illness would appear to be established (Kety et al., 1968; Wender et al., 1974; Baldessarini, 1977).

Previous successes in the identification of subgroups of psychotic individuals suffering from vitamin deficiencies, endocrine disorders, genetic diseases of metabolism, and other organic ailments also support this assertion (Sourkes, 1976).



Wagemaker and Cade (1977) have described the remission of psychotic symptomatology in a series of chronic, drug-resistant psychotic patients treated with an experimental course of 16 weekly hemodialyses. In a study of amino acids and peptides present in paired 1st and 16th dialysates from individual patients in that series, we have found evidence of two biologically separable subgroups, one in which high initial concentrations of [Leu5]-betah-endorphin, alone or in combination with [Met5] -betah-endorphin, declined 10- to 1000-fold during the regimen and one in which initially low levels of immunoreactive beta-Endorphin rose 2- to 4-fold by the 16th dialysis.



Heston (1970) used a different approach to examine the genetic as opposed to social possibility. He examined the children of schizophrenic mothers who had been permanently separated from their mother immediately after birth, and used as controls children born of normal mothers who had been put up for adoption in identical fashion. He found, among 47 children of schizophrenic mothers, 5 who were clearly schizophrenic, 13 who because of psychiatric illness were confined either in prisons or closed psychiatric hospitals, and 7 felons in prison. Among 50 children of nonschizophrenic mothers, he found only 2 in psychiatric hospitals and 2 felons in prison, and there were no schizophrenics in the group. Heston reasoned that unless social factors causing schizophrenia were already operant in utero, the schizophrenic mother relinquishing her child immediately after birth could have affected its development only by genetic endowment.




Studies of the occurrence of schizophrenia during the past 30 years have shown there is a genetic determinant in development of the disease. As the disease has an inherited predisposition, it seemed possible that a circulating, potentially dialyzable material causes the abnormalities. We therefore began dialyzing long-term chronic schizophrenic patients.



the first 31 patients dialyzed, two-thirds of the women and one-third of the men have had a salubrious response. Examination of the dialysate in some of the patients has revealed a high concentration of beta-endorphin, a material that can produce schizophrenic like behaviour.


Hemodialyses and Schizophrenia

Effects of Hemodialyses on Schizophrenic Symptoms and Dialysate Endorphin Levels


The use of hemodialyses in schizophrenia can be traced back to 1960 when a group of researchers in Switzerland noted improvement in three of five acute schizophrenic patients following hemodialyses (Thoelen et al., 1960; Feer et al., 1960). In 1977, Wagemaker and Cade in a preliminary study reported remission in chronic schizophrenic patients following weekly hemodialyses (Wagemaker and Cade, 1977).



There was a statistically significant reduction (p < 0.05) of hallucinatory behaviour of three female patients (patients 1, 2, and 5 with more than 10 years’ chronicity) following actual as compared to sham dialyses. This reduction, which was associated with a subjective sense of well-being, lasted only for 4 days. There was also a decrease in “somatic concern” and “anxiety” of the responders but it did not quite reach statistical significance (Table 3).



The concentrations of beta-endorphin immunoreactivity in concentrated dialysates of the patients are shown in Table 4. With the exception of dialysates from patient,4, the concentrations of beta-Endorphin are lower in the second dialysates (irrespective of clinical response). In the second dialysates of two nonresponders (patients 3 and 6) beta-Endorphin was not detected. It is also noted that the lowest level of beta-Endorphin was detected in the dialysates of the only paranoid patient (patient 3) in our sample.

Elsewhere, we have demonstrated the placebo effect of hemodialyses and suggestion on hallucinations (Malek-Ahmadi et al., 1980). Nevertheless, since the decrease in hallucinatory behaviour of our three patients was associated with reduced (although not statistically significant) somatic concern and anxiety on the BPRS, it is reasonable to conclude that repeated hemodialyses might have led to the reduction of less subjective symptoms such as conceptual disorganization and unusual thought content.



Review of the biochemical studies concerned with the etiology of schizophrenia suggests that endogenous production of a psychotoxin, derived from a naturally occurring substance, is involved in the psychopathogenesis of schizophrenia (Malek-Ahmadi and Fried, 1976). Recently, much attention has been given to beta-endorphin as a possible involved compound, and based on animal studies it has been proposed that excessive production of beta-endorphin may be responsible for some schizophrenic symptoms (Bloom et al., 1976). Compatible with this theory is the reduction in hallucinations of schizophrenic patients following injection of naloxone, a narcotic antagonist (Gunne et al., 1977; Watson et al., 1978).

Finally, animal studies have demonstrated that beta-endorphin and ACTH are simultaneously secreted in response to stress (Guillemin et al., 1977).

The effect of hemodialyses on chronic schizophrenia has yet to be conclusively determined by future double-blind controlled studies. If there is a subpopulation of schizophrenic patients responsive to hemodialyses, the remission may not necessarily be due to removal of beta-endorphin. Nevertheless, the involvement of Beta-endorphin as a possible



radioimmunoreactivity in the second dialysates. The results of our study are in agreement with the previous uncontrolled reports supporting the positive effects of hemodialyses on schizophrenic patients.

      1. Endorphin Deficit Theory

An exactly opposite view linking deficiencies of endorphins or endorphinlike compounds to schizophrenia proposed that low levels of opioid peptides by some as yet unknown mechanism trigger the functional psychosis at least in some individuals.


levels in body fluids have been inconsistent and probably unreliable, since valid techniques for unambiguously identifying specific endorphins and measuring their levels at extremely low concentrations were not yet available when most of the studies were done. Even if valid results are obtained, altered levels of endorphins in the body fluids of psychiatric patients may represent an epiphenomenon of their psychiatric illness (e.g.,


        1. Cortisol in Depression

This is not uncommon, since our recent studies (Rausch et al., 1980) have demonstrated disrupted circadian rhythms for the in vitro uptake of platelet [14C]serotonin and abnormal plasma cortisol levels in patients with major depression.


In our study intravenous methadone suppressed plasma cortisol and oral methadone suppressed urinary free cortisol. Naloxone has been found to increase plasma cortisol in man (Volavka et al., 1981; Naber et al., 1980a), suggesting that endorphins contribute to the tonic regulation of cortisol. 390


The relationship between the endorphin system and the hypothalamic-pituitary-.adrenal (HPA) axis is supported, in addition, by the results of animal studies, suggesting that ACTH and beta-endorphin share the same precursor prohormone peptide (Mains et al., 1977) and that they share coupled release (Guillemin et al., 1977; Rossier et al., 1980). Dexamethasone administration, however, has been shown not to suppress levels of jmmunoreactive beta-endorphin in man (Kalin et al., 1980). The apparent negative feedback by opiates on cortisol may be the result of negative feedback on corticotropin-releasing factor (CRF) and/ or ACTH secretion via opiate receptors located in the hypothalamus or pituitary (Simantov and Snyder, 1977; Gold et al., 1980). Other mechanisms for methadone-induced suppression of cortisol secretion are also possible, including direct suppression at the adrenal level, although this possibility seems unlikely in view of the reported suppression of ACTH in heroin addicts (Ho et al., 1977).

The inhibitory effect of opiates on cortisol may be particularly important in light of the findings in depressed patients of elevations in basal cortisol and transient cortisol suppression by dexamethasone. The etiology of this enhanced HPA activity is not well understood, although it has been suggested that diminished noradrenergic function is contributory (Sachar et al., 1980; Schlesser et al., 1979, 1980). Diminished endorphi-nergic tone theoretically could also contribute to the phenomenon. A decrease in endorphin activity might be produced by either subsensitive opiate receptors or diminished availability of opioid ligands. A decreased availability of opioid ligand might reduce a negative feedback on cortisol. If opiate receptors were subsensitive, a compensatory increase in opioids could occur; enhanced beta-endorphin release might produce a coupled increased ACTH release resulting in both an increased secretion of cortisol and resistance to the normal physiological suppression produced by dexamethasone.



We found plasma opioid activity, as determined by radioreceptor assay, to be elevated in mania as compared to depression in a medication-free manic-depressive patient studied across mood cycles. Although we cannot rule out the effects of circadian rhythm on the one afternoon sample when the patient completed the switch to depression, overall we observed no overlap between depressed and manic values. We also observed low plasma opioid activity during a highly agitated “mixed state” which preceded the emergence of depression, suggesting that in this patient motor activity was not the primary contributing factor for the high and low values found.

The origins of the opioid activity determined in the plasma may be derived from peripheral and/or pituitary origins.

In the second medication-free manic-depressive patient studied, disturbances in bowel function were observed to closely correspond with illness states. Mania was associated with constipation and diarrhea with depression, with the switch in clinical state closely paralleled by changes in bowel function. While constipation is most frequently associated with depression, diarrhea and other bowel disturbances have been reported in depressive illness (Engel, 1975). To our knowledge specific bowel dysfunction in manic-depressive illness has not been previously reported. Although the role of the endorphin system in normal bowel function is not fully understood, the gastrointestinal tract is abundantly replete with opiate receptors and opioid ligands (Ambinder and Schuster, 1979). In addition, opiate alkaloids are well known to decrease intestinal motility, producing constipation; diarrhea is a frequent symptom of opiate withdrawal (Jaffe and Martin, 1975). One might speculate that enhanced regional or systemic opioid activity might be associated with constipation; abrupt or persistent decrease in such opioid activity might, in turn, be associated with diarrhea. On the basis of this hypothetical endorphin-bowel relationship, the constipation observed during this patient’s manic periods and the diarrhea observed during the switch to and continuation of depression might reflect enhancement and diminution of endorphin system activity during mania and depression, respectively.



Intravenous methadone produced robust increases in plasma prolactin and decreases in plasma cortisol, while oral methadone treatment produced a marked decrease in urinary free cortisol. It is unknown whether the prolactin-stimulating effect of opiates is the result of a direct effect on prolactin-secreting cells or by putative interactions with dopamine neurons. This prolactin response to opiates may serve as a provocative test for evaluating opiate receptor function in vivo. The observed inhibitory effect of methadone on cortisol secretion supports a potentially clinically relevant relationship between the endorphin system and the HPA axis. It is hypothesized that decreased endorphin system function may be contributory to the HPA activation in depression.

        1. Endorphin Deficiency in Schizophrenia

There is evidence supporting an endorphin deficiency in schizophrenia has been accumulated. In three separate single-blind studies, psychiatric symptoms were decreased in schizophrenic patients following administration of the Met-enkephalin analog FK 33-824 (Jorgensen et al., 1979), [des-Tyrl]-y-endorphin (Verhoeven et al., 1979), or beta-endorphin (Kline et al., 1977).

In two independent double-blind, crossover experiments, Berger et al. (1980) and Gerner et al. (1980) found no clinically obvious improvement in schizophrenic symptoms following Beta-endorphin administration.


FK 33-824 is a Met-enkephalin derivative synthesized by Sandoz. It has the following amino acid sequence: Tyr-D-Ala-Gly-MePhe-Met(0)-ol. The amino acid sequence of Met-enkephalin is: Tyr-Gly-Gly-Phe-Met.

Jorgensen et al. (1979) used FK 33-824 in nine patients with chronic psychoses: eight chronic schizophrenics and one patient with alcohol hallucinosis. The patients had been hospitalized 7-15 yr. Their medication was continued but in addition they received, in a single-blind design, intramuscular injections of 1, 2, and 3 mg of this peptide on three consecutive days. A therapeutic effect was observed in six patients. Four showed a striking decrease in hallucinations and an increased sense of well-being. In two patients, no effect on hallucinations was observed, but they became more open and spontaneous, more than usually free in speech and euphoric. The effect persisted 4-7 days after the last injection. A rebound effect was observed in three patients. Initial improvement in these patients was followed by exacerbation, which in turn was followed by improvement. In an open pilot study, nine schizophrenic patients were treated with FK 33-824 on two consecutive days in a dose of 0.5 mg on the first and 1.0 mg on the second day, administered by infusion for 2 hr. Three patients refused treatment during or after the first infusion; of the remaining six patients, five improved remarkably on the first or second day. This antipsychotic effect continued for 28-168 hr (Nedopil and Ruther, 1979).

Since FK 33-824 has a terminal tyrosine residue, it therefore possesses morphinomimetic properties. It is unclear whether its therapeutic effect is related to these properties or to a “genuine” opiate receptor-independent antipsychotic action.



In an open design, a synthetic analog (Fk 33-824) of an endorphin fragment (Met-enkephalin) transiently improved psychotic symptoms in three of eight (J0rgensen et al., 1979) and in two (Krebs and Roubicek, 1979) chronic schizophrenics, and also had acute antidepressant effects in three of four depressed men (Krebs and Roubicek, 1979).


        1. Endorphin Deficiency in Depression

Gerner et al. (1980). however, did find a significant improvement in depressed patients 2 to 4 hr after beta-endorphin treatment.


Unipolar depression. In depression, platelet PGE1 formation is low but can be normalized by exposure to maximal ADP concentrations (Abdulla and Hamadah, 1975). Some depressives could have above-normal levels of a normal endorphin that can inhibit PGE1 biosynthesis. CHAPTER 4

Angst et al. (1979) treated in an open pilot study six female patients, four suffering from bipolar and two from unipolar depressions, with 10.0 mg beta-endorphin intravenously in a single-blind design. In all patients, antidepressant medication was discontinued at least 3 days before the trial injection. An improvement in depressive symptoms as measured by self-rating was observed in all six patients within the first 20-30 min. There was an initial increase of energy and elevation of mood with a decrease of anxiety, depression, and restlessness. These changes persisted in general for 2 hr. Thereafter, four patients relapsed. Two patients showed a switch from depression to hy-pomania and one patient to mania. This study concluded from these preliminary results that beta-endorphin may have some antidepressive properties and that beta-endorphin may convert depression to hypomania and mania.



The differing responses in manic and depressive illness may be due to differences in the dosage, route, and duration of administration of naloxone. Levels of “endorphinlike” activity in cerebrospinal fluid (CSF) are reported to be elevated in both depressed and manic patients, with a decrease following remission of manics (Lindstrom et al., 1978).

Synthetic human beta-endorphin has been given i.v. in an open design to two unipolar and four bipolar depressed females in doses up to 10 mg (Angst et al., 1979). Four patients had an acute antidepressant effect lasting several hours, and one unipolar and two bipolar patients switched into a hypomania within hours after receiving beta-endorphin. Two of three unipolar depressed males given 1.5-9 mg of synthetic human beta-endorphin i.v. in a single-blind design were reported to have symptomatic improvement lasting several hours (Kline et al., 1977).

Other findings that may bear on the role of endorphins in depression are the decreased sensitivity to somatosensory pain in some depressed patients (Davis et al., 1979; von Knorring, 1978) and the elevation of an endorphinlike fraction in the CSF of some bipolar depressed patients (Terenius et al., 1976). These findings suggest that some depressions are associated with elevated endorphins.

The proportion of depressed patients who improved after beta-endorphin was significantly greater than after placebo (p < 0.025, by Fisher’s exact test, with or without the schizoaffective patient, No. 10).

The typical depressed patient had more energy, increased sociability, and increased interest in other patients, staff, and ward activities after beta-endorphin infusion. These positive effects abated by the next morning in almost all cases. We found no hypomanic responses and no rebound increases in depression.

Subject No. 8. This middle-aged woman had been in a retarded unipolar depressed state for 3 months. She spent her days sitting somberly


The proportion of depressed patients who improved after beta-endorphin was significantly greater than after placebo (p < 0.025, by Fisher’s exact test, with or without the schizoaffective patient, No. 10).

The typical depressed patient had more energy, increased sociability, and increased interest in other patients, staff, and ward activities after beta-endorphin infusion. These positive effects abated by the next morning in almost all cases. We found no hypomanic responses and no rebound increases in depression.

Subject No. 8. This middle-aged woman had been in a retarded unipolar depressed state for 3 months. She spent her days sitting somberly on the ward, having to be. urged to engage in minimum activities or conversations. Much of her free time during the day was spent in bed, although she averaged only 4.5 hr of sleep nightly. She was reluctant to talk to her husband or consider plans after leaving the hospital. During her first infusion (beta-endorphin), she expressed hopelessness about the future and doubted that anything would help her. This cognitive set did not change until 2 hr after the session ended beta hr after receiving 4.3 mg of beta-endorphin). At that time, she spontaneously approached one of the investigators and stated she believed she had received “the real thing.”

Expanding on this at a normal rate of speech, she told of hopes of returning to work as an artist and taking a long-planned trip with her husband, whom she called on the phone and engaged in animated conversation. Her facies were bright, and she smiled for the first time since hospitalizaton. During the evening, she was active in the dayroom, engaging other patients and staff in conversation and games. That night, she slept her usual 4.5 hr and awoke in a mildly depressed state that deepened during the day. By the evening she was back to her previous inactivity. Following the next infusion (placebo), she showed no change in behaviour and complained that she had expected the same uplift as she had experienced previously. She then responded fully to 30 mg of tranylcypromine, appearing as she had during the several hours after beta-endorphin infusion.





Also, several reports have suggested that opiates may exhibit antidepressant effects in depressed patients, and there is evidence that beta-endorphin can temporarily alleviate depression and cause a switch from depression into mania (Angst et al., 1979).

Angst et al. (1979) report that bipolar affect disorder patients switch from depression to mania after receiving beta-Endorphin.292

Our observation that methadone alleviates depressive symptoms is supportive of a role for opioids in the regulation of affect, and is consistent with the work of Gerner et al. (1980) showing a mild antidepressant effect of beta-Endorphin in depressives.



There are anecdotal reports from the pre-psychotropic era of the efficacy of opiates in depression (Gold et al., 1977). In addition, the appearance of significant depression has been observed in opiate addicts after detoxification (Gold et al., 1979a; Gold and Byck, 1978). Some of these patients have been successfully treated with opiates and tricyclic antidepressants, suggesting that opiate discontinuation was similar to the discontinuation of effective psychopharmacologic maintenance treatment (Gold et al., 1979a). Administration of beta-endorphin to depressed patients has been reported to ameliorate depressive symptoms in some patients (Kline et al., 1977), and the opiate antagonist naloxone has been reported to ameliorate some manic symptoms (Gold and Byck, 1978; Janowsky et al., 1978). These data support the hypothesis that endogenous opioids are involved in the maintenance of pathological mood states.



We have utilized a neuroendocrine challenge paradigm to study in vivo, endogenous opioid systems in depressed patients. The normally pronounced increase in serum prolactin produced by morphine (Gold et al., 1978a; Tolis et al., 1978) was utilized to investigate the role of endorphins in major depression. We discuss our demonstration of a markedly blunted prolactin response in depressed patients in terms of a possible opiate receptor deficit in depression.



Of the affective disorders, manic-depressive illness and particularly the manic state has been investigated most thoroughly for endorphinergic involvement. Janowsky et al., (1978, 1979) reported that double-blind administration of naloxone was associated with a significant reduction in physician-rated manic symptomatology; this same group, however, in a replication study found significant improvement only in self-rated but not physician-rated symptomatology, although they observed improvement in 4 of the 10 manic patients studied (Judd et al., 1980). Emrich et al.

opioid peptides to manic patients, although Angst et al. (1979) in a nonplacebo-controlled study reported a switch to mania in three depressed patients following intravenous administration of beta-endorphin. Lindstrom et al. (1978) found elevations in specific CSF opioid activity fractions in medicated manic-depressive patients during mania as compared to depression. Pickar et al. (1980) reported elevations in plasma opioid activity in a cycling, medication-free, manic-depressive patient during mania as compared to depression.

There have been relatively few studies of naloxone administration in depressed patients. Terenius et al. (1977) administered naloxone three times a day for 6-12 days in five depressed patients without any effect on mood, although they did observe worsening in symptoms following the discontinuation of naloxone.



Kline and co-workers (Kline et al., 1977; Kline and Lehmann, 1979) found transient improvement in mood in several depressed patients in non-double-blind studies of intravenous beta-endorphin administration. Gerner et al. (1980) reported a statistically significant incidence of placebo-controlled improvement among 10 depressed patients following intravenous beta-endorphin. Pickar et al. (1981) found that intravenous beta-endorphin produced no significant behavioural differences from placebo in four depressed patients studied. Jorgensen et al. (1979) reported that individual schizophrenic patients experienced euphoria following parenteral administration of the peptidase-resistant synthetic enkephalin analog FK 33-824, although no similar study in affectively ill patients has been performed to date. Elevations in certain fractions of CSF opioid activity have been reported in some depressed patients (Terenius et al., 1977), although Naber et al. (1981) found no significant group differences in total CSF opioid activity between 41 depressed and 41 normal subjects.

This may hardly be surprising in light of the numerous studies implicating alterations in amine neurotransmitters (see reviews by Goodwin and Extein, 1979; Schildkraut, 1978; Murphy et al., 1978) and in the hypothalamic-pituitary-adrenal axis (Sachar et al., 1973; Carroll et al., 1976a,b; Schlesser et al., 1980; Brown and Shuey, 1980) in affective illness. Endorphins, however, are thought to act not only as neurotransmitters but also as neuromodulators, interacting with amine systems such as dopamine and norepinephrine (Iwamoto and Way, 1979) and with anterior pituitary neuroendocrine systems (Guidotti and Grandison, 1979; Holaday and Loh, 1979; Holaday et al., 1977).



3.3. Longitudinal Studies of Manic-Depressive Illness

In patient 1, plasma opioid activity was determined during manic, depressed, and switch phases of the patient’s illness (Table 1). The high opioid activity found when the patient was manic on day 1 of the study was followed by a low level during an agitated “mixed state” which accompanied a switch to depression. A further decrease in levels was found corresponding with the emergence of a severe motorically retarded depression that same afternoon. After a switch back to mania on the evening of day 2, relatively high opioid activity was found on days 3, 4, and 6 while the patient was manic. Samples collected during a 1-month period of a “stable” depression which followed this mania showed persistently low opioid activity. Mania was associated with significantly higher mean opioid activity than was depression (p < 0.01, Student’s t test, two-tailed).

In patient 2, self-rated symptoms of constipation and diarrhea recorded over 145 hospital days, including two switches from mania to depression, showed a consistent relationship with clinical state; mania was associated with constipation and depression with diarrhea (Fig. 6). Switches between clinical state were accompanied by abrupt changes in bowel activity.

Intravenous methadone produced somatic and mood changes in the six depressed patients studied, although there was only mild and transient anxiolytic and antidepressant effects. Previous studies of the behavioural effects of parenterally administered opiates have been performed largely in opiate-dependent populations. Mirin et al. (1976) found that in detoxified addicts, self-administered opiates produced prominent euphoric and anxiolytic effects early in the “addiction cycle” with diminution over repeated administration. Meyer et al. (1978) reported heterogeneity in the euphoric effects of self-administered opiates in detoxified addicts and observed that mood elevation was seen only in individuals who showed increased urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenethylene glycol (MHPG), concomitant with opiate administration. The relationship between opiate effects and noradrenergic function has also been supported by recent studies demonstrating the efficacy of the treatment of opiate withdrawal, including panic-anxiety symptoms, with clonidine, a drug that inhibits activity of the CNS noradrenergic locus coeruleus via a-adrenergic receptor stimulation (Gold et al., 1978b, 1979a,b).



Although neither drug produced marked antidepressant effects, methadone rapidly produced mental clouding, sleepiness accompanied by a slight decrease in anxiety and mild euphoria; in contrast, beta-Endorphin produced somatic sensations such as “tingling” and feelings of warmth, but no sleepiness, sedation, or euphoria.

The one patient who was treated with oral methadone had previously responded with slight self-rated improvement following intravenous methadone. The effects of oral methadone were suggestive of an antidepressant effect. The clinical improvement that occurred during the first 3 weeks of treatment included changes in affect as well as improvement in motoric retardation and hyposomnic sleep pattern. The return of some symptomatology after 2 weeks of treatment may have been indicative of a developing tolerance phenomenon. An attempt to sustain this improvement by increasing the methadone dosage was not successful; increased somatic disturbances were the most prominent effect. Methadone discontinuation over 1 week did not produce significant withdrawal signs. The patient eventually responded well to ECT, a treatment that has been shown to increase levels of endorphins in the plasma (Emrich et al., 1979).

Opiate alkaloid treatment of mental disorders is an old idea (Bucknill and Tuke, 1858) with renewed interest since the discovery of the endogenous opioid system (Gold et al., 1977; Comfort, 1977). Fink et al. (1970) used the mixed narcotic agonist-antagonist cyclazocine in an open study of the treatment of depressed patients, and found clinical improvement in 8 of the 10 patients studied, including patients who had been treatment-resistant to tricyclic antidepressant therapy. It is not known whether this effect was the result of the antagonist or agonist effects. Lehmann et al., (1971) reported clinically significant antidepressant effects of 2 weeks of non-placebo-controlled treatment with a combination of meperidine and d-amphetamine in 5 of 12 depressed patients studied. While psychodynamic speculation emphasizes the roles of chronic opiate administration in addicts in relieving tension (Reichard, 1947; Savit, 1954) and in experiencing euphoria (Wieder and Kaplan, 1969), experimental studies of addiction have consistently reported that chronic opiate administration results in generalized dysphoric states with increased levels of anxiety, depression, and hostility (Wikler, 1952; Haertzen and Hooks, 1969; Martin et al., 1973; Mirin et al., 1976).



The results of our pilot study of oral methadone treatment suggest that stimulation of opiate receptors by an opiate agonist that is clearly accessible to the CNS can ameliorate depressive symptomatology. It is possible that this effect is the direct result of enhancement of the exogenous opioid system activity or the result of beneficial interaction with other neurotransmitter systems. In either case a depression-related deficit in endorphin system activity, perhaps resulting from decreased levels of available peptide or from diminished sensitivity or number of opiate receptors, might be suggested. Further controlled trials with opiate agonists are needed to evaluate this as a treatment strategy. Whether the negative behavioural effects of opiates seen in addicts would occur in a time-limited treatment of opiate-naive patients is unknown. It is possible that different opiate effects (e.g., tolerance/dependence or mood effects) may be differentially mediated at the opiate receptor level. Research into the biochemical substrates of different opiate actions may enable the development of opiates with selective and advantageous behavioural effects.

Recently, Extein et al. (1980) reported blunted prolactin response to parenteral morphine administration in depressed patients in comparison to normal controls and patients with personality disorders. This finding suggested down-regulation of endorphin system function in depression, possibly through receptor subsensitivity. Further studies are needed to investigate the possibility of opiate receptor differences between patient and normal groups, perhaps using similar opiate-neuroendocrine challenges.



However, in an earlier series a significant positive correlation did exist between the degree of depressive symptomatology and the concentrations of fraction I Endorphins (Almay et al., 1978). Furthermore, high concentrations of fraction I endorphins have been observed in patients with depressive disorders (Lindstrom et al., 1978).



4.7. 5-HIAA, HVA, and MOPEG in CSF

In patients with low concentrations of fraction I endorphins in CSF, we found significantly lower concentrations of 5-HIAA and HVA in CSF, indicating a low turnover in the serotoninergic and dopaminergic systems (Table 2). However, as can be seen in Table 1, the relationship with the serotoninergic systems seems to be the most important. Furthermore, it appears that there is also a relationship with MOPEG, indicating a relationship with the central noradrenergic systems.



Patients with low concentrations of fraction I endorphins in CSF were found to have significantly higher values on all subscales in the Zuckerman Sensation Seeking Scale.

      1. Circadian Rythme to Beta Endorphin

There appears to be a circadian rhythm for Beta-endorphin, the activity of which has been found to be low in the morning and relatively high in the evening, as reflected in the plasma of normal healthy subjects. Normal circadian rhythms may be altered during the diseased state.


      1. Endorphins Acting on the Hypothalamus

Accumulated evidence points to an action of the endorphins at the level of the hypothalamus rather than affecting directly the pituitary gland.Page 27


      1. Stress leads to release of ACTH and beta-endorphin

Page 29

The observation that severe stress leads to simultaneous and proportional release into the circulatory system of both ACTH and beta-endorphin was taken as an indication that they are coordinately regulated and concomitantly stored (Guillemin et al.. 1977).


Panksepp et al. (1978) administered beta-Endorphin s.c. to chickens and found that it significantly decreased the frequency of distress vocalizations. However, the s.c. route of administration was not nearly as effective as i.v.t. Injection.




Emotional stress raises immunoreactive endorphin levels over 2-fold (Teschemacher et al., 1980).

Since ACTH, beta-lipotropin, and beta-endorphin seem to be released simultaneously from the pituitary (Krieger et al., 1979), one would expect that the kinds of stress that elicit ACTH release also trigger release of the opioid peptide.


The discovery of endorphins led to the observation that endogenous opioids are released during acute stress. Simultaneous release of beta-endorphin and ACTH has been reported in animals during acute stress (Guillemin et al., 1977). Further, it has been observed that animals become hypotensive within minutes of an i.v. injection of morphine sulfate (Evans et al., 1952) or an i.v. or intracisternal injection of Beta-endorphin (Lemaire et al., 1978; Bolme et al., 1978). This hypotensive response can be reversed or prevented by the opiate antagonist, naloxone (Dashwood and Feldberg, 1978). From these observations, it seemed possible that the release of Beta-endorphin may be responsible for hypotension during acute stress. In animal experiments, Holaday and Faden (1978) have shown that naloxone rapidly reverses the hypotension that results from hemorrhage or injection of endotoxins (for details, see Chapter 9). On the basis of these observations, Peters et al. (1981) successfully used naloxone in patients with endotoxin shock to raise the blood pressure.

It is postulated that Beta-adrenergic stimulation releases opioid peptides (the origin of which is uncertain) (Wright, 1981). The released endorphins inhibit the action of both catecholamines and renin and in turn are responsible for hypotension. Opiate antagonists counter these effects and thus stabilize blood pressure.

One other area where this knowledge has been utilized is that of spinal cord injury. Faden et al. (1981a) used naloxone to treat cats subjected to cervical spinal trauma. Naloxone treatment improved the hypotension resulting from acute trauma and spinal shock and as a result, the animal also showed better neurological recovery. This finding implicates endorphin-induced hypotension in the pathophysiology of spinal cord injury resulting from spinal trauma. Faden et al. (1980), on the basis of their experimental work, postulated that endorphin-induced hypotension during spinal shock probably results from interaction between endorphin systems and central parasympathetic centers.

Recently in animal studies,-thyrotropin-releasing hormone (TRH), a partial physiologic opiate antagonist, has been found to improve the neurologic recovery after spinal trauma (Faden et al., 1981b) and the cardiovascular function in experimentally induced endotoxic and haemorrhagic shock (Holaday et al., 1981).



      1. Endorphins, Pain and Analgesia

4.1. Pain

However, the best evidence for the involvement of the endorphin-opiate receptor system lies in the area of pain modulation.

Page 30

Naloxone is capable of reversing the analgesia produced by means other than the administration of exogenous opiates. Thus, analgesia produced by electrical stimulation or acupuncture has been shown to be antagonized by naloxone in animals (Akil et al., 1976; Pomeranz and Chiu, 1976) and humans (Adams, 1976; Mayer et al., 1977). Placebo produced analgesia has also been shown to be reversed by the administration of naloxone (Levine et al., 1978a).

Good success in the relief of intractable pain in patients by electrical stimulation via implanted electrodes in the periventricular gray region has been reported by Richardson and Akil (1977). A multipolar electrode was implanted near the posterior aspect of the third ventricle, medial to the nucleus parafascicularis and in close proximity to the posterior commissure. The electrode was then connected to a Medtronics receiver implanted in the chest. A Medtronics stimulator allows patients to selfadminister current at desired parameters (amplitude, frequency, etc.). Significant or complete pain relief with periventricular stimulation was noted by patients. This analgesia was blocked by naloxone in 80% of the cases.

The stimulation-produced analgesia was effective for a period of several months and in some cases even years. During surgery an intraventricular catheter was used to withdraw samples of ventricular fluid prior to and at intervals after electrical stimulation. RIAs were performed on these samples. While a less than 2-fold increase was seen in enkephalinlike immunoreactivity (Akil et al., 1978a), a 15-fold increase in beta-endorphinlike immunoreactivity was observed (Akil et al., 1978b).


Terenius had identified “fraction I” in CSF as an enkephalinlike peptide. Its level is higher in pain-insensitive subjects and lower in pain-sensitive subjects (Terenius et al., 1976). Schizophrenics are known to be insensitive to pain (Marchand et al., 1969). Naltrexone treatment seems to increase the responsiveness of schizophrenic patients to pain (Davis et al., 1979). Fraction I is also low in chronic psychotics


Many excellent reviews discuss the role of endogenous opiates in pain modulation (Editorial, 1980; Kosterlitz, 1979). In animals, intraventricular or i.v. injection of enkephalins has been reported to produce profound analgesia of a short duration (Belluzzi et al., 1976; Loh et al., 1976). Graf et al. (1976) noted that beta-Endorphin produced analgesia 50 times more potent than that of morphine. Moreover, evidence suggests that i.v. administration of Beta-endorphin (Catlin et al., 1977) or i.v. Met-enkephalin and beta-Endorphin (Hosobuchi and Li, 1978) may result in analgesia in human subjects, suggesting their role in pain modulation: Using radioimmunoassay, Beta-endorphin levels were measured in the plasma of 22 women undergoing labor and parturition and in the plasma of their neonates. The level of immunoreactive beta-Endorphin in the plasma of women undergoing labor was found to be significantly elevated (Csontos et al., 1979).

Additional evidence for the function of endorphins in pain modulation has come from a number of neurophysiological studies. Electrical stimulation of discrete areas of the diencephalon and brain stem in rats has been reported to produce analgesia (Reynolds, 1969). In humans, electrical stimulation of the periaqueductal and periventricular areas has been reported to produce beneficial results in chronic intractable pain (Ho-sobuchi et al., 1977). Similarly, Richardson and Akil (1977) have reported that even normal pain perception can be blocked by the stimulation of periaqueductal gray matter. A recent study (Hosobuchi et al., 1979) indicated that electrical stimulation of periaqueductal gray matter in six patients with chronic pain induced pain relief in three patients with pain of peripheral origin and not in the other three with pain of central origin. A concomitant increase of beta-endorphins in the ventricular fluid and CSF has been noted with pain relief (Akil et al., 1978a,b). All these findings suggest that electrical stimulation of the brain increases endorphins and induced analgesia similar to that of morphine.



If the opioid peptides present in the CNS have physiological function, it would follow then that the opiate antagonists naloxone and naltrexone should reverse the analgesic effects of electrical stimulation. Surprisingly, the findings of such investigations have produced contradictory results. An increase in endorphins has been noted in the ventricular CSF after electrical stimulation of periaqueductal gray matter (Hosobuchi and Li, 1978; Hosobuchi et al., 1979), and pain relief obtained by electrical stimulation of periaqueductal gray matter in three of the patients was completely reversible by naloxone while only partial reversal was reported by others (Akil et al., 1976). Similarly, naloxone blocks the antinociceptive effect of electrical stimulation of periaqueductal gray matter of the rat brain (Akil et al., 1972). However, others have reported negative results (Pert and Walter, 1976). The possibility of naloxone enhancing pain perception has been investigated with both positive (Jacob et al., 1974; Frederickson et al., 1976) and negative (Goldstein et al., 1976) results.

5.2. The Syndrome of Congenital Insensitivity to Pain

This syndrome has been studied in order to establish the relationship between endogenous opiates and pain perception (Yanagida, 1978). Intravenous injections of 2-10 mg naloxone relieve the insensitivity to pain, indicating that the total absence of pain may be related to a permanent hyperactivity of endogenous opiate system. In a comparative study, reflex of the lower limb as a correlative index of pain sensation in normal subjects and with patients having congenital insensitivity to pain before and after naloxone or placebo injections.



In control subjects, no significant variation of this threshold was observed either after placebo or after naloxone. But the baseline flexion-reflex threshold, which was 350 times higher in the congenital pain insensitivity patients, decreased dramatically by 67% within 10 min after the injection of naloxone. Dunger et al. (1980) support the hypothesis that congenital insensitivity to pain could be related to a tonic hyperactivity of a morphinelike pain-inhibiting system, and this can be antagonized by naloxone. They reported (Dunger et al., 1980) the clinical picture of a disordered hypothalamic function in a 13-year-old boy with abnormal control of temperature, appetite, and thirst, hyperprolactinemia, and inappropriate vasopressin release, along with pain insensitivity. Upon administration of naloxone to rectify the presumptive disturbance of the opioid peptide system, central analgesia and other associated abnormalities improved.

The finding that acupuncture-induced analgesia can be reversed by naloxone provided impetus to search for the release of endorphins concomitant with the analgesic effect (Sjolund and Eriksson, 1976; Pom-eranz and Chui, 1976; Sjolund et al., 1977). In fact, electroacupuncture was reported to increase beta-endorphin immunoreactivity in six patients undergoing thoracic surgery and these patients did not need any further analgesics (Abbate et al., 1980). The beta-endorphin level fell slightly or remained constant in controls. Low-frequency electroacupuncture effectively alleviated recurrent pain in 10 patients (Clement-Jones et al., 1980). Basal levels of beta-endorphin and Met-enkephalin in the CSF of these patients were not different from those in pain-free control subjects. After electroacupuncture, all patients showed significantly increased CSF Beta-endorphin levels and no change in Met-enkephalin levels, thereby suggesting that the analgesia observed after electroacupuncture in patients with recurrent pain was apparently mediated by the release into the CSF of the endogenous opiate, beta-endorphin, and not by Met-enkephalin. These changes are not intrinsic to electroacupuncture, since heroin addicts undergoing acupuncture for the treatment of withdrawal symptoms showed a rise in Met-enkephalin without any change in Beta-endorphin

(Clement-Jones et al., 1979). On the other hand, Sjolund et al. (1977) observed an increase in the opiate activity in a CSF fraction that did not correspond to either beta-Endorphin or Met-enkephalin. This fraction may be pro-opiocortin. As the bioassay of beta-endorphin also measures pro-opiocortin, increased beta-Endorphin levels noted by many after electroacupuncture may merely reflect increased pro-opiocortin in CSF with subsequent formation of beta-Endorphin. The finding that naloxone completely reverses the electroacupuncture analgesia of low-frequency but not high-frequency stimulation led Cheng and Pomeranz (1979) to suggest that acupuncture analgesia may be mediated by at least two mechanisms: one, endorphin related and naloxone reversible and the other, serotonin related and naloxone nonreversible.



Hypnosis is used for its analgesic effects. Investigations have been carried out to establish the role of endogenous opiates in hypnotic analgesia. One single-blind study (Stephenson, 1978) indicated that naloxone reversed hypnosis-induced analgesia, thus implicating endogenous opiates. However, other reports (Goldstein and Hilgard, 1975; Barber and Mayer, 1977; Nasrallah et al., 1979) demonstrated that naloxone in doses of 0.4 to 50 mg failed to alter the hypnosis-induced analgesia. These results do not provide definitive evidence that endorphins are involved in hypnosis-induced analgesia.

Thus, their hypothesis that naloxone exerts an antiplacebo effect in placebo responders remains unproven.

As previously mentioned, pain may be mediated by both an endorphin system activated by low-frequency electrical stimuli and sensitive to naloxone and by a serotonin system activated by high-frequency electrical stimuli but insensitive to naloxone (Cheng and Pomeranz, 1979). In addition, substance P may also be involved. Substance P produces analgesia when administered to mice in very small doses intraventricularly and this effect can be blocked by naloxone. At higher doses, naloxone blocking of analgesia is lost. At higher doses, substance P produces hyperanalgesia with naloxone and analgesia when combined with baclofen, a drug that enhances y-aminobutyric acid. These results indicate that substance P may have a dual action in brain, releasing endorphins at very low doses and directly exciting nociceptive pathways at higher doses (Frederickson et al., 1978).



Frequently, many of these youths display a rather striking indifference to pain, raising the question in view of the above whether there may be an overactivity of the opioid elements and its possible relationship to learning and behavioural difficulties as well as to dysphoric states.




The Importance of the Endorphin Systems in Chronic Pain Patients


Pain is an emotional experience, as universal as anxiety. Probably, pain is the most common single symptom in clinical practice. However, when we discuss pain, we do it in relation to bodily complaints, and the pain is often discussed as if localized in some part of the body. Thus, pain is easily regarded as a sign of somatic disease, both by physicians and by patients.

However, pain is an emotional experience that may be evoked by noxious stimulation of some part of the body, but the pain experience may also be evoked without the corresponding peripheral stimulation. In fact, pain is as common in psychiatric disorders as in somatic disorders (Merskey and Spear, 1967). In clinical practice, pain is often seen as a prominent symptom in anxiety neurosis, in Briquet’s syndrome, in schizophrenic psychosis, and in depressive disorders.

Acute pain is, in many respects, very like the experience of anxiety, while chronic pain has many of its characteristics in common with the depressive syndrome (Sternbach, 1974). In chronic pain syndromes, evoked by either organic or psychogenic factors, the characteristics of the depressive syndrome—sadness, meaninglessness, and hopelessness—are often present and in depressive disorders pain is a common and often prominent symptom. In patients with depressive disorders, hospitalized at a psychiatric ward, pain is usually found in about two-thirds of the patients. At an outpatient department the frequency is probably even higher. Thus, it has been suggested that chronic pain syndromes and depressive syndromes share some common pathogenetic mechanism (Sternbach, 1974; von Knorring, 1975).



The physiological mechanisms involved in pain perception, pain interpretation, and pain experience are complex and several different transmitter systems are involved. In the intrinsic modulatory systems in the nucleus gigantocellularis, nuclei raphe, locus coeruleus, nucleus ruber, substantia nigra, and limbic system, y-aminobutyric acid, dopamine (Moroni et al., 1978; James and Starr, 1979; Barasi, 1979), substance P (Michelot et al., 1979), acetylcholine (Kapatos and Zigmond, 1979), norepinephrine (Aghajanian, 1978), and serotonin (Messing and Lytle, 1977; Rodgers, 1977) are found as neurotransmitters. Furthermore, the endorphin systems, the beta-endorphin systems, the dynorphin systems, and the enkephalin systems are involved. The beta-endorphin and dynorphin systems are more likely to be main candidates in controlling pain sensitivity, mood, and behaviour than the multicentered enkephalin systems (von Knorring et al., 1980). In a situation like this, it seems probable that the intrinsic balance between the different transmitter systems is the most important factor that regulates pain sensitivity and pain experience.



The clinical differentiation of pain syndromes of predominantly organic versus psychogenic origin is often difficult. Clear-cut psychogenic pain syndromes may be seen during hypnosis, while clear-cut organic pain syndromes may be seen in laboratory settings. However, in clinical practice both psychogenic and organic factors are often of importance.



Two personality inventories were used. The Eysenck Personality Inventory (Eysenck and Eysenck, 1964) covers two broad aspects of personality—extra version and neuroticism. The inventory has earlier been found useful in pain patients (Bond and Pearson, 1969). The Zuck-erman Sensation Seeking Scale was originally constructed to measure differences in the ability to withstand sensory deprivation (Zuckerman, 1971, 1979). It is composed of five subscales measuring thrill and adventure seeking, experience seeking, disinhibition, boredom susceptibility, and general sensation-seeking. In earlier studies, relationships have been found with the amplitude-intensity slope in VEP and with the platelet enzyme, monoamine oxidase (von Knorring, 1978; Zuckerman, 1979).



4.1. Distribution of Fraction I Endorphins in CSF

In a small series of healthy volunteers, fraction I endorphins in CSF have been found to be normally distributed with a mean around 0.9 pmole/ ml CSF. In the present series of 80 chronic pain patients, we found a positively skewed leptokurtic distribution with a mean of 0.90 pmole/ml CSF and a median of 0.80 pmole/ml CSF (Fig. 1). Thus, there is an overrepresentation of patients with low concentrations of fraction I endorphins. In this series, there is no significant sex difference and there is no significant correlation with age (age range 20-60 years, r = -0.06).




Possible Relationships of Fraction I Endorphin Concentrations in CSF with Clinical, Psychophysiological, Neurophysiological, and Biochemical Variables in Chronic Pain Patients (a)

Independent variable (b) Multiple r Overall F Significance

Fraction II endorphins 0.34 6.38 p < 0.02

Diagnosis 0.45 6.00 p < 0.01

5-HIAA 0.51 5.42 p < 0.01

MOPEG 0.54 4.71 p < 0.01

Pain threshold (PTc) 0.56 4.04 p < 0.01

Pain level 0.58 3.61 p < 0.01

HVA 0.59 3.24 p < 0.01

Amplitude-intensity slope 0.60 2.84 p < 0.02

Total depression score 0.60 2.48 p < 0.05

Pain threshold (PTDS) 0.60 2.19 p < 0.05

Tolerance level (TLDs) 0.60 1.97 n.s.

Tolerance level (TLc) 0.60 1.76 n.s.

(a) Chronic pain patients, N = .50. Data evaluated using stepwise multiple regression. (b) Independent variables include: age, sex, CSF concentrations of fraction II endorphins, 5-HIAA, HVA, and MOPEG, clinical diagnosis (pain syndromes of predominantly organic or psychogenic origin, respectively), pain level as estimated by means of a visual-analog scale, total depression score as evaluated by means of the Comprehensive Psychopathological Rating Scale, pain threshold and tolerance level as evaluated by means of electrical stimulation via saline electrodes (DS, discrete step stimulation increase; C, continuous stimulation increase), and amplitude-intensity slope in evoked potentials.

When patients, according to clinical judgement of a neurologist and a psychiatrist, were divided into groups with chronic pain syndromes of predominantly organic origin and psychogenic origin, patients with chronic pain syndromes of predominantly organic origin were found to have significantly lower concentrations of fraction I endorphins. In this group, 70% of the patients had concentrations of fraction I endorphins below the mean while only 41% of the patients with chronic pain syndromes of predominantly psychogenic origin had such low values (Fig. 2). This difference is significant at the 2% level (x2 = 6.37, p < 0.02).



However, it is possible that these low concentrations of fraction I endorphins appear after the onset of the syndrome. In three patients with acute pain syndromes of organic origin, high concentrations were found (mean 1.9, range 1.2-2.3 pmole/ml CSF). Furthermore, in an earlier series we were able to demonstrate a significant negative correlation between the duration of the pain syndrome and the concentration of fraction I endorphins in CSF (Almay et al., 1978).



The experience of pain is a complex phenomenon, involving several aspects, such as pain perception, pain interpretation, and pain experience. In these complex mechanisms several transmitter systems are involved at different levels. Thus, it seems clear that an intricate functional balance must exist between these systems. To determine one of these transmitter systems in the CSF is a compromise, necessary due to practical and ethical limitations in clinical research. However, from the studies reported here it seems meaningful to relate the endorphinergic activity in CSF to clinical and psychophysiological parameters. The method used in these

From the present results, it appears that a functional relationship exists between the serotoninergic, the dopaminergic, the noradrenergic, and the endorphinergic systems.



The most pronounced difference that has been most consistent throughout the studies is the difference in concentrations of fraction I endorphins between patients with chronic pain syndromes of predominantly organic and predominantly psychogenic origin. The pain experience in psychogenic and organic pain is very similar and the experienced pain levels do not differ between the groups. The degree of depressive symptomatology is also the same in both groups. However, it is still possible that physiological differences may occur between the groups. In earlier studies (Shenkin, 1964; Lascelles et al., 1974), patients with organic pain syndromes were found to have significantly higher values of plasma cortisol than patients with psychogenic pain syndromes.

Our results indicate that in organic pain syndromes the concentrations of fraction I endorphins decrease with the duration of the pain syndrome. The same changes do not seem to occur in psychogenic pain syndromes. Instead, these patients often have very high concentrations of fraction I endorphins, usually above those found in healthy volunteers (Lindstrom et al., 1978; Almay et al., 1978; von Knorring et al., 1982).



Fraction I has also been found to be related to the serotoninergic, the dopaminergic, and the noradrenergic activity in CSF. Furthermore, during treatment with a rather specific serotonin reuptake inhibitor, zimelidine, the pain levels decreased and significant changes occurred in both 5-HLAA and fraction I in CSF.

Patients with chronic pain syndromes of predominantly organic origin were found to have low concentrations and the concentrations tended to decrease with the duration of the pain syndrome.

many clinical correlations. However, patients defined as complainers from their results on the Eysenck Personality Inventory were found to have significantly lower concentrations of fraction II in CSF.

Furthermore, they were found to have a greater discrepancy between reported symptoms and observed signs in physician’s rating, indicating a tendency to experience the symptoms intensively and to communicate them freely. They also had lower pain thresholds and lower tolerance levels. Thus, these patients, who usually are poorly accepted by medical staff, may have physiological and biochemical characteristics that may explain why they experience their symptoms so intensively.

      1. Electrostimulation, Acupuncture and Opioids

5.1. Factors That Alter the Levels of Endogenous Opioids in

Cerebrospinal Fluid

beta-Endorphin levels increase in the CSF after electrostimulation of the medial thalamus or periaqueductal gray area (Akil et al., 1976; Ho-sobuchi et al., 1977), or after acupuncture (Mayer et al., 1977). Enkephalinlike substances also increase in CSF after electrostimulation of the periaqueductal gray area (Akil et al., 1976). Modulation of the pain pathways by endogenous opioids may lead to their enhanced release extra-cellularly during activation of the pathway.

Electroshock and insulin shock also raise plasma endorphin levels (Krieger et al., 1979).


    1. Neurotransmission

The finding that endorphins inhibit the release of various neurotransmitters, along with the demonstration that opiate receptors can have a presynaptic location, has given rise to the concept that the enkephalins and perhaps beta-Endorphin are neuromodulators, i.e., the degree to which they are released modulates the release of classical neurotransmitters.

Page 43

There are indications that endorphins can be regarded as neurotransmitters or neuromodulators. High endorphin concentrations are found in brain areas involved in pain conduction, motor activity, and regulation of mood and affect, such as the limbic system structures. Animal experiments have shown that, in addition to a morphinomimetic effect, the endorphins exert an influence on behaviour which may not be mediated by opiate receptors.



Nevertheless, our results do suggest the possibility that the opioid system, either directly or via other neurotransmitters such as acetylcholine, dopamine, or norepinephrine, may be involved in the regulation of affect.283


Future Scope for Endorphin Research


Advances in peptide neuropharmacology have led to the postulation of a novel method of communication within neurons. Barker et al. (1978) observed that certain effects of enkephalins did not conform to the previously known forms of neuronal communication. At certain sites enkephalins acted as neurotransmitters, but most often acted in a manner that was different from traditional neurotransmitter action. These workers referred to this form of communication as “neuromodulation,” which they defined as “the alteration of receptor coupled membrane conductance, without direct activation of such conductance.” It is observed that enkephalins at certain sites do not directly dominate membrane excitability by altering a specific ionic conductance as a neurotransmitter does but rather modulates the subsynaptic action of neurotransmitter-coupled events. Thus, “neuromodulators” modify subsynaptic coupled mechanisms but cannot change the neuronal membrane potential by themselves; they require the presence of neurotransmitters. At times, opioids act as neurohormones, such as the well-established effects of beta-endorphin (Caine, 1979).




The modification of subsynaptic coupled mechanisms may involve some alterations with respect to sodium channels. Zieglgansberger et al. (1976), during their experiments on enkephalin-induced inhibition of cortical neurons, observed that enkephalins did not hyperpolarize the cell but instead blocked the sodium influx elicited by the excitatory neurotransmitters by acting directly at the level of sodium channels in the membrane. Thus, They reduced or inhibited the action of excitatory neurotransmitters by modifying subsynaptic mechanisms that are coupled with release of excitatory neurotransmitters. It appears that binding of enkephalins to receptors results in the alteration in permeability of membrane to sodium ions and this may be one of the ways in which enkephalins act at the cellular level. The other mechanisms involving a second messenger such as the prostaglandins and cyclic AMP have been considered in detail by Horrobin in Chapter 4 of this volume.

Opioid receptors have been identified at the level of presynaptic membranes. It is assumed that enkephalin binding at these sites would cause an alteration in the impulse-related release of the particular neurotransmitter. This is the probable way in which enkephalins modify the dopaminergic activity in the striatum, the details of which are considered in the latter part of this chapter.



      1. Opiates Increase Dopa, Antipsychotics and Adrenal Activity

Accordingly, some investigators continued to examine the effects of systemic injections of the brain opiates, and successful reports began to appear: Szekely et al. (1977) reported analgesic effects, Plotnikoff et al. (1976) demonstrated increased activity in a Dopa potentiation test

These investigators injected either Met-enkephalin or [D-Ala2]-Met-enkephalin into mice intraperitoneally (i.p.) and evaluated the effects in several activity paradigms. Both forms of enkephalin produced increased activity in the Dopa potentiation test at all doses tested (0.1, 1.0. and 10.0 p.g/kg) after 30 min and at the two larger doses after 60 min. A slight but significant increase in the serotonin potentiation test for activity was also reported at both time intervals for the 10 pLg/kg dose. Further, decreased footshock-induced fighting at lower doses and a slight reduction in audiogenic seizures were observed. . .

Extein et al. (1979) reported that i.p. injections of FK 33-824 in rats produced apomorphine-like stereotyped behavior that was antagonized by naloxone as well as neuroleptics, thus suggesting that FK 33-824 can activate opiate and dopamine receptors in the brain.


The most basic form of behavioral modulation that occurs probably involves alterations in the daily activities of the organism such as general activity level, eating and drinking, etc. The first study in the literature to observe any form of behavioral effect after systemic injection of opioid peptides was that of Plotnikoff et al. (1976). These investigators injected either Met-enkephalin or [D-Ala2]-Met-enkephalin into mice intraperitoneally (i.p.) and evaluated the effects in several activity paradigms. Both forms of enkephalin produced increased activity in the Dopa potentiation test at all doses tested



In the adrenal, the enkephalinlike peptides are released into the bloodstream as well as into medullary areas on stimulation (Wilson et al., 1980). In this tissue, enkephalins seem to be acting both as neurotransmitters and as neurohormones.

Both opioids and neuroleptics stimulate dopamine metabolism in the nigrostriatal system. Opiates (Clouet and Ratner, 1970; Smith et al., 1972), endorphins (Van Loon and Kim, 1978), and haloperidol and chlorpromazine increase dopamine turnover in rat striatum (Anden, 1972; Lloyd et al., 1973). The chronic administration of morphine (Iwatsubo and Clouet, 1975) or haloperidol (Schwartz et al., 1978) increases the sensitivity of the postsynaptic dopamine receptor in the caudate nucleus. Haloperidol and other neuroleptics block the postsynaptic dopamine receptor by direct competition with dopamine (Kebabian et al., 1972), while opioids do not (Kuschinsky and Hornykiewicz, 1972). The inhibitory effect of neuroleptics on dopamine-sensitive adenylate cyclase activity in post-synaptic membranes can be demonstrated in vitro (Clement-Cormier et al., 1974). Opiates, however, do not have a direct effect on dopamine stimulation of adenylate cyclase (Iwatsubo and Clouet, 1975). The firing of nigrostriatal neurons is enhanced both by morphine (Iwatsubo and Clouet, 1977) and by haloperidol (Bunney et al., 1973). The turnover of dopamine in both the nigrostriatal pathway and the limbic dopamine system is enhanced by opiates and neuroleptics (Westerink and Korf, 1975). Although neuroleptics act postsynaptically and opioids presynaptically, both classes of drugs enhance the activity of dopaminergic neurons.

Neuroleptics (Marco et al., 1976), opiates, and endorphins (Moroni et al., 1979) inhibit GABA turnover in the substantia nigra. Similarly, the involvement of the postsynaptic muscarinic neurons of the striatum in the feedback loop is indicated by an increased activity of these neurons due to the blockade of dopaminergic inhibition. Neuroleptics (Racagni et al., 1976), opiates, and endorphins (Moroni et al., 1978) increase the turnover of acetylcholine in the striatum and also in the limbic system.

In another dopaminergic pathway—the hypothalamic A-12 cells that inhibit neurons containing releasing factors for pituitary hormones—the inhibition is antagonized by neuroleptics (Van Vugt et al., 1979) and opioids (Deyo et al., 1979), with an inhibition of dopamine turnover. (There is no neuronal feedback loop in this tissue.) Both classes of drugs, therefore, enhance the release of the pituitary hormones under inhibitory control by dopamine.



The conclusion reached from these data is that neuroleptics and opioids elicit very similar biochemical effects in dopaminergic systems (nigrostriatal, limbic, and hypothalamic dopamine pathways) and in associated systems such as the muscarinic system in the striatum and nucleus accumbens and the GABA system in the substantia nigra (Table 3). Indeed, chronic treatment with neuroleptics has been shown to affect both brain enkephalins and plasma endorphins. The level and rate of biosynthesis of Met-enkephalin in rat striatum are increased after chronic treatment with haloperidol, chlorpromazine, or pimozide (Hong et al., 1978). In both animals and man, daily haloperidol treatment elevates plasma endorphins to very high levels (Hollt et al., 1980). These findings suggest that endogenous opioids participate in the action of neuroleptic antipsychotic activity.


Besides guinea pig ileum, morphine-sensitive adrenergic functions have been found in the vas deferens of mouse (Henderson et al., 1972).





Autoradiographically identified opiate receptors are widely distributed throughout the brain’s major noradrenergic nucleus, the locus coeruleus (LC) (Simon, 1975; Atweh and Kuhar, 1977; Kuhar, 1978). Stimulation of these opiate receptors by morphine and endogenous opioid peptides has been demonstrated to produce a marked inhibition of LC firing rate and block increases in LC firing rate normally demonstrated after a painful stimulus in single neuronal electrophysiological recording studies (Korf et al., 1974; Aghajanian, 1978; Bird and Kuhar, 1977).

We hypothesize that this interaction between opiates and noradrenergic areas like the LC is responsible for many of the physiological and affective changes associated with opiate administration and may provide the pathophysiological substrate mediating naturally occurring panic anxiety states and opiate withdrawal (Gold and Kleber, 1979; Gold et al., 1979c).

The catecholamines were among the first compounds to be linked with emotion, based on the similarities between the physiological effects of adrenalin and those occurring during fear and rage (Maas and Landis, 1971; Frankenhaeuser, 1975; Levi, 1972; Redmond et al., 1977; Schild-kraut, 1965). Numerous subsequent studies of dopamine and norepinephrine (NE) have produced little conclusive evidence linking these catecholamines to specific emotions. Recent data from studies of electrolytic lesions and electrical stimulation of a major brain NE nucleus, the LC, in Macaca arctoides suggested specific alterations in fear-or anxiety-related emotions (Gold and Redmond, 1977; Huang et al., 1975; Redmond et al., 1977, 1978; Gold et al., 1979a,c; Gold and Pottash, 1980). The same behaviours that were noted in field studies of this species to be associated with impending aggression, conflict, or uncertainty were increased by discrete electrical stimulation of the LC, and after specific pharmacological activation of NE neurons by piperoxane, an a-adrenergic antagonist that in low doses acts predominantly at a2 receptors in the vicinity of NE cell bodies to increase neuronal firing rates (Gold and Redmond, 1977; Gold et al., 1979c).



A possible link with anxiety or fear in humans is supported by observations that piperoxane (Goldenberg et al., 1947; Soffer, 1954) and a similar compound (yohimbine; Holmberg and Gershon, 1961) produce severe anxiety in humans. The fact that many volunteers refused a second administration (Holmberg and Gershon, 1961) would support the interpretation that the “threat” of a second drug administration in our study, as well as the conditioned signal of electrical shock risk, both produced states of anxiety or fear.

Further work is necessary to increase the specificity of existing evidence that anxiolytic compounds act by interfering with NE function, and that important effects of opioids in particular are due to inhibition of noradrenergic nuclei.

In summary, recent data suggest that the LC is involved in naturally occurring panic and anxiety (Gold et al., 1978c, 1979a,d). Identical behaviours in monkeys are produced by fear-or anxiety-provoking stimuli, by compounds that activate brain NE systems, and by LC electrical stimulation alone. These same behaviours are eliminated by compounds that reduce LC activity or block its projections. Since drugs activating the LC produce anxiety, and drugs blocking effects of LC electrical stimulation are anxiolytic in man, brain NE systems may be involved in anxiety, and anxiolytics may work by inhibiting LC function (Gold et al., 1979a,c,d; Gold and Redmond, 1977; Redmond et al., 1978).

We hypothesize that this interaction between opiates and noradrenergic areas like the LC is responsible for many of the physiological and affective changes associated with opiate administration and may provide the pathophysiological substrate mediating opiate withdrawal (Gold et al., 1978b,c, 1979a,b,c,d; Gold and Kleber, 1979).

Opiate receptors, through which opiate alkaloids and peptides exert their pharmacological effects, appear to have an important role in modulating the functional activity of the LC (Kuhar, 1978). We propose that exogenous opiate administration (e.g., heroin or morphine) stimulates opiate receptors to inhibit the LC and inhibit the release of endogenous opioid peptides. The absence of exogenous opiates and the inability of

in opiate withdrawal (Gold et al., 1978b,c). The hypothesis that increased LC firing rate produced by abstinence is the pathophysiological substrate for opiate withdrawal has recently been tested in man, rodent, and nonhuman primates (Crawley et al., 1979; Redmond et al., 1979; Gold et al., 1978b,c, 1979b,c; Gold and Kleber, 1979).

The anatomical connections of the LC are more than adequate to place it in a central position in opiate action and withdrawal symptomatology. It has numerous and important projections to the cortex, the limbic system, the medullary and spinal centers affecting cardiovascular sympathetic activity, bowel and sphincter activities, and to the spinal cord, hypothalamus, and other important brain neurotransmitter systems (Dahlstrom and Fuxe, 1964; Loizou, 1969; Morrison et al., 1979; Korf et al., 1973; Jones et al., 1977; Sakai et al., 1977). The LC also receives afferents from all sensory modalities, noradrenergic and serotoninergic neurons, the hypothalamus, and other areas. This anatomy, our studies with nonhuman primates (Gold et al., 1979c; Redmond et al., 1977, 1978; Gold and Redmond, 1977), the experiences reported in the literature with drugs that specifically augment LC activity (Goldenberg et al., 1947; Gold and Kleber, 1979), and other recent data with endogenous opioid peptides (Young et al., 1977; Simon, 1975; Kuhar, 1978) support an important role for the LC in the feeling state, cardiovascular, sympathetic peripheral changes, and the parasympathetic systems to produce the visceral manifestations of opiate action and withdrawal (Gold et al., 1979c).

Anxiety, fear, increased heart rate, increased blood pressure, yawning, diarrhea, nausea, anorexia, insomnia, irritability, increased respiratory rate, restlessness, scratching, pupillary dilatation, and perspiration are seen in man or primates given drugs (e.g., piperoxane, yohimbine) that markedly activate the LC (Gold et al., 1979a,c), primates receiving weak electrical stimulation of the LC (Redmond et al., 1977, 1978, 1979), or man in acute opiate withdrawal (Gold et al., 1978b,c). These behaviours and physiological responses elicited in primates by dangerous situation, LC stimulation, and drugs that activate LC firing and NE release provide a preliminary confirmation of an LC-opiate withdrawal hypothesis. These data suggest that piperoxane administration and LC stimulation may be useful as a primate model for the signs and symptoms of opiate withdrawal, as well as panic anxiety. It has been demonstrated that opioid peptides have significant and consistent effects on the pontine LC, opposite to those produced by electrical stimulation of the LC or pharmacological stimuli. Endorphins and opiates also have an opposite effect on these electrically and pharmacologically elicited behaviours and physiological signs in nonhuman primates. Drugs that inhibit the function of the LC, are nonopiates, and block these elicited behaviours and visceral phenomena, may be hypothesized to be useful in the medical treatment of opiate withdrawal (Gold et al., 1978b,c).

Recent developments have led to the characterization of receptors on the cell bodies of the LC that are specific for NE, epinephrine (E),y-aminobutyric acid (GABA), substance P, as well as the opiates. Agha-

et al., 1979c). Blockade of the alpha2 receptor by piperoxane results in a release from inhibition and resultant large increases in noradrenergic firing rate as well as NE release and turnover (Maas et al., 1976, 1979). As endogenous and exogenous opiates are known to inhibit LC activity, release from inhibition may explain the behavioural and visceral similarities between opiate withdrawal, LC stimulation, and piperoxane administration.



Our studies in primates have led to the hypothesis that the majority of the signs and symptoms of opiate withdrawal are mimicked by procedures that increase the functional activity of the noradrenergic LC (Gold and Kleber, 1979). If the LC is critical to opiate withdrawal, then drugs that have opposite functional effects should be useful in the treatment of opiate withdrawal in man. Opiates have this effect and are useful in withdrawal. Endogenous or synthetic analogs of endogenous opioid peptides should be useful as well but still produce tolerance and dependence.

Administration of the putative neurotransmitters NE, E, and GABA, all of which inhibit the functional activity of the LC in specific doses, should be effective in withdrawal, but the administration of these agents peripherally in sufficient quantity to permeate the blood-brain barrier limits their usefulness. The benzodiazepines, presumed to block the activity of the LC’ by interaction with the inhibitory GABA system and GABA receptors on the pontine LC, should, if given in high enough doses, have an effect on opiate withdrawal. The postsynaptic beta-adrenergic antagonist propranolol has been reported by some but not other investigators to have an effect on reducing opiate withdrawal.

Recent work in our laboratory with the a-adrenergic agonist clonidine has suggested the possibility that clonidine may be an effective treatment of opiate withdrawal by its specific effects on the LC (Gold et al., 1980b). Clonidine blocks and reverses the effects of piperoxane and LC stimulation in the primate.

Clonidine produces effects on blood pressure, pulse, respiration, and other visceral responses commonly associated with opiates and opposite to those seen in withdrawal. We have reported that clonidine administration rapidly and consistently causes a reduction or abolition of opiate-withdrawal signs and symptoms in man (Gold et al., 1978b,c, 1979a,b,c,d, 1980a,b). These data support the hypothesis presented here and other hypotheses and studies in the literature that have attributed opiate effects and opiate withdrawal to interactions with catecholamine systems (Eidelberg, 1976; Roberts et al., 1978; Herz et al., 1974; Aghajanian, 1978). This hypothesis and these clinical data are supported by our recent demonstration of potent antiwithdrawal efficacy for the clonidine analog, lofexidine (Gold et al., 1980c).



The pattern of signs and symptoms exhibited by patients withdrawing from opiates and by patients experiencing spontaneous attacks of panic anxiety is similar (Sweeney et al., 1980 a,b,c); this pattern is also observed in humans after the administration of drugs (e.g., piperoxane, yohimbine) that markedly activate the noradrenergic nucleus LC (Cedarbaum and Aghajanian, 1976 a,b), and after abrupt discontinuation of chronic clonidine administration (Gold et al., 1979c). These similarities suggest a possible common endorphin-noradrenergic mechanism mediating the syndromes of opiate withdrawal and panic anxiety. However, there are no reports of direct and quantitative comparison of these two syndromes.

Ten opiate addicts (8 males, 2 females) were studied. Test battery included vital signs, the Addiction Research Center Inventory for Weak Opiate Withdrawal, the Spielberger State Anxiety Inventory, and analog self-rating scales for anxiety, fear, irritability, unpleasantness, anger, and euphoria (Sweeney et al., 1980a,b).

This battery was administered to opiate addicts twice daily during a baseline period of methadone maintenance, then every 6 hours for 36 hours after the abrupt discontinuation of methadone. For the panic anxiety patients, the battery was administered twice daily for 7 medication-free days, and immediately upon the onset of a panic attack. All patients had at least two spontaneous panic attacks during the study period.

The two groups did not differ during the baseline period. During withdrawal or panic, both groups showed significant increases in heart rate, blood pressure, temperature, tremulousness, anorexia, insomnia, restlessness, and gastrointestinal discomfort (p < 0.01). The opiate withdrawal patients demonstrated a significantly greater elevation of anger and irritability than did the panic anxiety patients, who, in turn, demonstrated a significantly greater elevation of fear ratings (p < 0.01).

All opiate withdrawal patients responded to treatment with clonidine with a rapid decrease in symptoms. Three of the panic anxiety patients with previous unsuccessful responses to imipramine were given clonidine during a panic anxiety attack. Two of these three patients showed nearly complete alleviation of panic symptoms, while the third patient showed a significant but partial response to clonidine. These findings suggest a common neurobiological mediation of opiate withdrawal and panic anxiety (Gold et al., 1979a,c).



The discovery of opioid peptide transmitters and delineation of their interactions with the noradrenergic LC has led to our proposing that opiate effects on mood and physiological responses result from the opiate-induced inhibition of the LC. Withdrawal of opiates removes this “tonic” inhibition of the LC and could readily result in a piperoxane-like release from inhibition. Endorphin deficiency or relative inability of endorphin-mediated inhibition to effectively turn off the LC might be responsible for the signs and symptoms of panic.

This hypothesis is also supported by recent data suggesting that clonidine is an efficacious nonopiate treatment (Gold and Kleber, 1979; Gold et al., 1980d; Paalzow, 1974) for opiate withdrawal.

In 1977, Urea and colleagues reported that intracerebroventricular injection of Met-enkephalin produced epileptiform activity in rats.

In addition, it was associated with an increase in dopaminergic activity; dopamine turnover, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) content in the striatum also showed simultaneous increases. These effects are similar to those produced by y-hydroxybutyrate (GHB). GHB-treated animals serve as an experimental animal model of petit mal epilepsy (Godschalk et al., 1977). This epileptogenic activity in the ECoG and the behavioural effects were blocked by high doses of naloxone and by anticonvulsants that are specifically active against petit mal, i.e., ethosuximide, trime-thadione, and sodium valproate.

It is possible that GHB-induced seizure activity in ECoG, related behavioural changes, and dopamine release may be related to GHB-opiate receptor interaction. However, there are some differences in the duration of paroxysmal activity induced by enkephalin and GHB (Snead et al., 1980).

A related point of interest is the relatively higher doses of naloxone required to block the epileptic effect of Leu-enkephalin than that required to block the analgesic effect. This finding suggests that the former property of enkephalins differs in its site of action than the latter. Frenk et al. (1978) postulated that the enkephalin-induced seizure activity is mediated by 8 receptors in the dorsomedial thalamus, while the analgesic activity is mainly mediated by mu receptors.



        1. Tardive Dyskinesia and parkinsons


Enkephalin, Naloxone, and [Des-Tyr1]-y-Endorphin in

Tardive Dyskinesia


Tardive dyskinesia (TD) is a potentially irreversible hyperkinetic syndrome primarily localized in the muscles of the oral and facial regions, and it may also occur in the limbs and trunk. It develops during or following long-term neuroleptic treatment, especially in elderly patients (Crane, 1973; Tarsy and Baldessarini, 1976; Gerlach, 1979). The pathophysiological mechanisms underlying the syndrome are only partly clarified. Reversible TD appears to depend on reduced dopaminergic neurotransmission during neuroleptic treatment, followed by adaptive phenomena such as postsynaptic dopamine receptor hypersensitivity and cholinergic hypofunction (Tarsy and Baldessarini, 1976).




In recent years, beta-endorphin (beta-lipotropin61_91) and its peptide fragments have been found to affect dopamine-mediated mechanisms (Van Loon and Kim, 1978; Watson et al., 1979) and appear to be involved in the regulation of neuropsychiatric functions. beta-Endorphin, as well as the smaller peptide fragments enkephalin (beta-lipotropin61_65) and [des-Tyr1]-y-endorphin (DTyE; beta-lipotropin62_77), have been used in the treatment of schizophrenia and depression, with ambiguous results (see elsewhere in this volume).

Enkephalinergic neurons have been identified in the caudate nucleus and globus pallidus, and enkephalin receptors seem to be localized on nigrostriatal dendrites participating in the regulation of the release of dopamine (Kuhar et al., 1973; Pollard et al., 1977; Costa et al., 1978).



Naloxone, however, reversed reserpine-induced akinesia, rigidity, and tremor in rats (Diamond and Borison, 1978), diminished tremor in one of our patients, and thus may have some antiparkinsonian effect when given in high doses.



There is evidence that reversible TD depends on primary reduced dopamine neurotransmission induced by neuroleptic treatment, followed by adaptive phenomena including a relative dopaminergic overactivity perhaps involving a disturbed balance between dopaminergic and cholinergic functions.

However, there has been no consistent effect of either the Met-enkephalinergic compound, FK 33-824, or DTyE in TD or in parkinsonism. FK 33-824 seems to have anti-hyperkinetic and parkinsonian-aggravating effects, when added to concurrent, relatively intense antidopaminergic neuroleptic treatment, suggesting that this compound may have some modulatory influence on dopamine mechanisms, perhaps corresponding to the effect of GABA

      1. Opiates increase serotonin activity

Page 62

Opioid peptides were shown to have a moderate cerebrovascular permeability that should allow penetration of the blood-brain barrier in 3-11 min, with a steep increase in plasma concentration of unbound peptide.

A slight but significant increase in the serotonin potentiation test for activity was also reported at both time intervals for the 10 ug/kg dose.


As concerns the serotoninergic systems, patients with low concentrations of 5-HIAA in CSF have earlier been shown to have certain characteristics, including vulnerability and a tendency toward suicidal behaviour (Asberg et al., 1976). It still remains to be seen whether patients with low concentrations of endorphins in CSF will show the same characteristics. The relationship between the norepinephrin metabolite MOPEG and the endorphins could be expected from the following: (1) the noradrenergic neurons of the locus coeruleus are inhibited by the systemic or local administration of opiates or enkephalins (Aghajanian, 1978), and (2) clonidine, an a-adrenergic agonist, has been used successfully in the treatment of morphine withdrawal (Gold et al., 1978), indicating a functional relationship between the endorphin and the noradrenergic systems.

With respect to the relationships between the endorphin concentrations in CSF and certain personality traits, both the relationships found are of some interest. The relationship between the endorphinergic activity and a sensation-seeking behaviour is interesting since a relationship seems to exist between a sensation-seeking behaviour and a tendency to abuse of morphine (Zuckerman, 1979). Thus, a low turnover in the endorphinergic systems, indicating a low production of the body’s own morphine, may be one of the reasons for morphine abuse. Furthermore, a sensationseeking behaviour has been found in patients with low platelet monoamine oxidase, indicating a low turnover in the serotoninergic systems. Thus, these results also indicate a functional relationship between the serotoninergic and the endorphinergic systems. The fact that patients identified as complainers from personality inventories have been found to have lower concentrations of fraction II endorphins in CSF is of interest. The fact that biochemical and physiological differences may explain the behaviour of these patients may help to give a better understanding of the patients, who usually are poorly accepted by medical staff.



      1. Phenylketonuria: phenylalanine and β-endorphin were significantly correlated

Previous animal and human studies have suggested an analgesic effect of phenylalanine involving endogenous opioid peptides. We found a trend towards a higher β-endorphin level in phenylketonuria (median 26.0 pM, range 13.0–37.8) than in the control subjects (20.6 pM, 12.7–28.0), P = 0.13. Cerebrospinal fluid concentrations of phenylalanine and β-endorphin were significantly correlated (r = 0.68, P = 0.008). The results support the hypothesis that phenylalanine modifies the central endogenous opioid system.

Neuroscience Letters

Volume 129, Issue 1, 5 August 1991, Pages 131-133

Neuroscience Letters

Correlation between cerebrospinal fluid phenylalanine and β-endorphin in patients with phenylketonuria

Author links open overlay panelFlemming W.Bach

12Jytte BieberNielsen4JetteBuchholt3HansLou4FlemmingGüttler


Peptides and Amino Acids in Human Hemodialysate



Molecular knowledge of mental disease dates from the discovery in 1934 of increased levels of phenylalanine and phenylketones in the urine and plasma of phenylketonuric patients (Foiling, 1934)


For example, phenylketonuric patients are mentally retarded, have imbalances of neurotransmitter and neuroendocrine biochemistry, suffer from inadequate protein synthesis at crucial developmental times, and may have alterations of normal bone growth or pigmentation (Tourian and Sidbury, 1978). By analogy, any metabolic lesion that leads to psychosis as its primary symptom must be biochemically quite subtle, as most psychotic patients do not have overt physical findings or mental retardation.

    1. Neuroendocrine interactions with Opioid Molecules

The medically and nonmedically used psychoactive drugs can induce changes in the physiological functions of various neurons in the CNS. The present data suggest that direct interference with the degradation of enkephalins in the CNS may be part of the complex mechanism of action of various antipsychotic drugs.


Recent advances in opiate research have provided a new dimension in the understanding of neuroendocrine control of pituitary function (Meites et al., 1979). The arcuate-median eminence region of the hypothalamus contains the highest concentration of beta-endorphin in the human brain (Wilkes et al., 1980), indicating that beta-endorphin may play a role in endocrine control through the hypothalamic axis. Opioid antagonists have been employed to elucidate the role of beta-endorphins in endocrine regulation.



Opioid polypeptides function in conjunction with other hormonal systems and these complex relationships elude an easy answer regarding their role.

Hormones from the anterior and posterior lobes of the pituitary gland are essential for the regulation of peripheral endocrine organs, water metabolism, and other processes of importance in the maintenance of homeostasis. The release of anterior pituitary hormones is controlled by both releasing and release-inhibiting factors, produced in the hypothalamus and transported to the pituitary gland via the bloodstream (portal vascular system between hypothalamus and pituitary gland). Neurohypophyseal hormones produced in the hypothalamus are transported via neurons to the posterior pituitary lobe where they are stored.

In addition to their influence in the periphery, several hormones from the anterior and posterior pituitary lobes have an effect on the central nervous system (CNS) which can be revealed from their influence on certain types of behaviour. Unlike their peripheral effects, however, the influence of these hormones on behaviour does not require the entire molecule. The influence of these hormones on behaviour can be exerted independent of their endocrine effects. Pituitary hormones may serve as precursor molecules from which behaviourally active fragments are split off by enzymatic action. Peptides such as these that affect the CNS are termed neuropeptides (de Wied, 1969; de Wied et al., 1974). The discovery of the endorphins has given rise to a new class of peptides which can be defined as neuropeptides.


Endorphins in Psychiatric Research and Treatment





We based our strategy on the observation that a number of animal studies have focused on the effects of opiates (morphine, etc.) and the opioidlike peptides (endorphins) on neuroendocrine function, whereas other studies have used narcotic antagonists (naloxone, naltrexone) to explore opioid-neuroendocrine interactions (Bruni et al., 1977; Shaar et al., 1977; Tolis et al., 1975).

In animal studies, interactions between opioids and prolactin, growth hormone, luteinizing hormone, and follicle-stimulating hormone have been defined. In rodents, morphine as well as beta-endorphin and Met-en-kephalin have been shown to increase serum prolactin and growth hormone levels, while naloxone, a relatively specific narcotic antagonist, has been found to decrease these levels (Tolis et al., 1975; Shaar et al., 1977). Furthermore, in man, serum prolactin has been found to be increased by morphine and related opiates and opioids (Tolis et al., 1975).

In addition, there is growing evidence of a linkage between the opioid peptides and the hypophyseal-adrenal axis (Mains et al., 1977). It is likely that beta-lipotropin is the precursor for both beta-endorphin and ACTH, since beta-endorphin and ACTH are secreted simultaneously by the anterior pituitary, and adrenal glucocorticoids regulate endorphin production in cultured pituitary tumor cells. There are also reports that exogenous opiates reduce cortisol levels and block the cortisol response to stress (Guillemin et al., 1977; Sabol, 1978; McDonald et al., 1959; Ho et al., 1977; George et al., 1974).

Overall, serum growth hormone was minimally, although significantly elevated as compared to placebo following naloxone infusion. Diagnosis, or the presence of antipsychotic medications did not appear to significantly influence the degree of the naloxone-induced rise in serum growth hormone.

In addition, we compared the effects of naloxone on serum growth hormone levels and on behaviour and mood in the 12 manic patients in whom we obtained blood samples. We evaluated an arousal-activation subscale of the Beigel-Murphy Mania Scale and applied the euphoria-grandiosity subscale, and noted that increases in serum growth hormone were inversely related to changes in the sum of the euphoria-grandiosity plus arousal-activation subscale scores, although this relationship was not quite statistically significant.

They found elevated endorphin levels in the cerebrospinal fluid of schizophrenic patients, an observation suggesting that endorphins may be implicated as a factor in schizophrenia. On the basis of this hypothesis, Gunne et al. (1977) treated a small number of schizophrenic patients with the narcotic antagonist naloxone, administered intravenously in a dosage of 0.4 mg, and reported this regimen to exert an antihallucinatory effect.

Other investigators (Kurland et al., 1977; Volavka et al., 1977; Davis et al., 1977; Janowsky et al., 1977) promptly sought to replicate these observations in double-blind controlled studies in which naloxone was administered intravenously in increased dosages, but were unable to substantiate the earlier observations reported by Gunne et al. (1977). In subsequent attempts, Terenius and colleagues were also unable to replicate their original work in a double-blind controlled study. Mielke and Gallant (1977), employing the more potent narcotic antagonist naltrexone in a dosage of 50 to 250 mg administered orally in patients free of active medication for 2 weeks prior, found this antagonist also to be ineffective in ameliorating the symptoms of schizophrenia. However, some uncertainty prevails despite these negative observations. Emrich et al. (1979) and Berger et al. (1979), in controlled double-blind studies employing a dosage of 4 to 10 mg naloxone, reported results similar to the earlier results reported by Gunne et al. (1977). Lehmann et al. (1979) in single-and double-blind studies observed the responses of seven male chronic schizophrenic patients to 10 mg naloxone and reported statistically significant improvement of psychotic behaviour as determined by ratings obtained on the Brief Psychiatric Rating Scale (BPRS) before and 6 hr after the injection of the antagonist. Additionally, adrenocorticotropin (ACTH) blood levels were also determined before and li and 6 hr after injection, with the greatest improvement noted in the patients displaying the most pronounced diurnal variation of ACTH levels. No improvement was observed in the patients who had no diurnal changes.

These findings led Lehmann et al. (1979) to hypothesize, despite the negative reports of Davis et al. (1977), Volavka et al. (1977), and Kurland et al. (1977), that positive and negative behavioural responses to naloxone may depend, as possibly do many placebo responses in general, on the relative stress produced by experimental or therapeutic interventions. Moreover, the placebo response can be accounted for by a measurable physiological factor, i.e., increased endorphin secretion. The basis of their hypothesis was the suggestion by Mains and Eipper (1978) and Roberts and Herbert (1977) that there is a common precursor peptide that gives rise to both ACTH and beta-endorphin. Guillemin et al. (1977) found



that both beta-endorphin and ACTH are concomitantly secreted in response to acute stress. They state, “Both hormones possess common and identical regulatory mechanisms.” Thus, it seems highly probable that because of the “yoking” of the two peptides, measurement of one would provide an index to the other.

The uncertainty as to the relation of the endogenous opioid peptides to schizophrenia led Gold et al. (1979) to examine this from another perspective, namely., the effect on prolactin secretion. The effect of dopamine in the tonic inhibition of serum prolactin and the known action of neuroleptic drugs at dopaminergic synapses have led to measurements of prolactin secretion (Meltzer, 1977; Langer et al., 1977). Gold et al.

(1979), utilizing primates and man, were able to demonstrate that the effect of naloxone on prolactin was in the anticipated direction. Their prolactin data were also in agreement with animal data from other model

In fact, their data suggest that large doses of opiate antagonists may augment dopaminergic activity. Gold et al. (1977) state, “The effects of opiates and endorphins in increasing serum prolactin and of naloxone in decreasing it, support the hypothesis that endorphins may function as a prolactin stimulating factor.” Additional evidence suggesting this possibility is the increased prolactin level in patients following infusion of 3 to 6 mg beta-Endorphin (Lehmann et al., 1979).






The emergence of new syndromes possibly associated with a disorder of the endogenous opioid peptide system and having psychiatric implications and in which the narcotic antagonists may be utilized therapeutically, is suggested in a recent report (Dunger et al., 1980) on a 13-year-old male, who was well until age 4 1/2 years at which time there was a rapid onset of obesity associated with decreased activity. As the patient’s disorder progressed, there occurred a constellation of symptoms suggesting a syndrome characterized by disordered hypothalamic function. Among the more striking manifestations was a marked diminution in the sense of pain perception, with the patient on occasion burning himself and unaware of the hazard, and in undergoing diagnostic air encephalography and other painful clinical procedures and displaying no apparent signs of discomfort. behaviour and mood changes were also associated early in his illness with hypersomnia. When awake, his mood was euphoric and his speech monotonous, punctuated by outbursts of hysterical laughter and accompanied by repetitive mannerisms. During the previous 2 years he had been sleeping less, but inactivity, euphoria, and dull affect persisted. On the WISC scale with allowance made for his slow responses, he scored 95-100. Other manifestations of disturbed hypothalamic function were reflected in abnormal control of temperature, appetite, and thirst. Hyperprolactinemia was also observed as well as inappropriate vasopressin release and other endocrinological changes as reflected in hormonal assays.

The presence of the analgesia suggested the use of naloxone. Although the naloxone reversed central analgesia, altered urine fluid and electrolyte excretion, modified the hormonal response to gonadotropin releasing and thyrotropin-releasing hormones, and improved the auditory and visual reaction times with a restoration of normal diurnal variation

      1. Growth Hormone and Prolactin

On the other hand, the opiates, morphine and methadone, are well known to be potent stimuli of growth hormone (GH) and prolactin (PRL) secretion in the rat (Kokka and George, 1974).

Since Met-enkephalin and beta-Endorphin bind to the opiate receptor and have potent morphinelike activity in various biological assays, the possibility was raised that the endogenous opioid peptides, besides their well-known analgesic potency and activity as behavior modulators, could also be involved in the neuroendocrine control of GH and PRL secretion.


Relationship of Opiate Peptides to Neuroendocrine Functions



Although, as described above, endorphins and their analogs can stimulate GH and PRL secretion in experimental animals and man, such data do not prove the physiological role of these peptides in the control of neuroendocrine functions.


Animal studies have shown that beta-Endorphin administration increases plasma levels of prolactin and growth hormone (Rivier et al., 1977; Dupont et al., 1977; Chihara et al., 1978) similar to morphine. However, Catlin et al. (1980) noted that i.v. infusion of beta-Endorphin increases serum prolactin but not growth-hormone or cortisol in depressed subjects and withdrawing methadone addicts in a placebo-controlled double-blind study. In humans, however, Lal et al. (1979) have shown that neither naloxone nor levallorphan has any effect on basal serum prolactin concentration nor apomorphine-induced growth hormone secretion. The mediation of these effects by opiate receptors is supported by the finding that pretreatment with naloxone or naltrexone, the specific opioid antagonists, blocks the opioid peptide-induced (Chihara et al., 1978; Shaar et al., 1977) as well as morphine-induced (Bruni et al., 1977) release of these hormones. Administered alone, naloxone and naltrexone produce significant decreases in prolactin levels in monkeys (Gold et al., 1978) and rats (Grandison and Guidotti, 1977; Bruni et al., 1977). Similarly, Volavka et al. (1979a) also observed that naloxone did not have any effect on serum prolactin in normal men. The discrepancies between the findings on prolactin in animals and man indicate that the response may be species specific.



Control and depressed patients did not differ significantly in age or sex distribution. Morphine infusion produced marked, significant increases (p < 0.05) in serum prolactin 30, 60, 90, 120, and 180 min after infusion in controls.



Both exogenous opiates and endogenous opioid peptides have been shown to be potent stimulators of secretion of the pituitary hormone prolactin in animals and man (Gold et al., 1977, 1978a; Tolis et al., 1978; von Graffenried et al., 1978). Morphine in the dosage range used here has been reported to produce large and reliable increases in serum prolactin in normal subjects (Tolis et al., 1978). This prolactin secretion is thought to be mediated by the inhibitory effect of activation of the opiate receptors that have been identified on dopaminergic neurons (Gold et al., 1978a).

Inhibition of’ dopamine’s tonic inhibition of prolactin secretion would account for increased secretion of prolactin (Gold et al., 1978a) reported here and elsewhere (Gold et al., 1977, 1978a; Gold and Byck, 1978). Thus, the absent or blunted increase in serum prolactin following morphine infusion in patients with major depressive disorder reported here may reflect abnormalities in central endorphin or dopamine systems.

However, the blunted prolactin response in patients with normal baseline prolactin is consistent with an opiate receptor deficit in major depressive disorder, with decreased number of opiate receptors or decreased opiate receptor sensitivity or presence of an excess of endogenous opiate antagonist.

Preliminary work shows significant elevation of serum prolactin in depressed patients after infusion of 5 mg methadone, which is about twice as potent as morphine (Extein et al., 1979). This again supports an opiate receptor subsensitivity in major depression.



As endorphins and corticosteroids have a common precursor, these endorphin response data may relate to other neuroendocrine data demonstrating discrete and reproducible abnormalities in depression (Gold et al., 1980c). These and other findings (Gold et al., 1977, 1978a, 1979a; Tolis et al., 1978; von Graffenried et al)., 1978; Gold and Byck, 1978; Kline et al., 1977; Janowsky et al., 1978)suggest dysfunction in central endogenous opioid peptide systems in depression and support the need for further exploration of neuroendocrine abnormalities reported and possible antidepressant effects of exogenous opioids and endogenous opioid peptides and analogs in patients with primary depression.

Before the discovery of the endogenous morphinelike compounds, the endorphins in the brain, physicians had used exogenous opiates for the treatment of pain, depression, and manic-depressive illness. In addition, exogenous opiates were widely used for their anxiolytic, euphoric properties as well as their ability to produce and maintain an organismic sense of well-being. The ability of opiates to insulate users from real, imagined, or anticipated threat, the distribution of endogenous opiate receptors, and recent behavioural studies in man and nonhuman primates have suggested that endogenous opiates modulate panic in man.

      1. Estrous Cycle

3.3a. Estrous Cycle. Measurement of the beta-Endorphin content in 16 specific hypothalamic and extrahypothalamic nuclei during stages of the estrous cycle reveals that significant variations occur only in suprachiasmatic and arcuate nuclei and the median eminence (Fig. 7). In the arcuate nucleus, which contains the highest beta-endorphin content of all brain nuclei, the afternoon of proestrus coincides with a 50% decrease in beta-endorphin content compared to the mean content on all other days of the cycle. In contrast, the beta-Endorphin content of the suprachiasmatic nucleus and median eminence is increased by 100 and 65%, respectively, on the afternoon of proestrus when compared to the mean content on all other days of the cycle while in the suprachiasmatic nucleus, the content remained elevated throughout estrus. In both arcuate nucleus and median eminence, by the day of estrus, values returned to those seen on the first days of the cycle.

Since opiate peptides have been demonstrated to reduce the turnover of DA in the median eminence (Ferland et al., 1977) and DA levels in the median eminence are decreased on the afternoon of proestrus (Crowley et al., 1978), it is possible that the increased beta-endorphin content of median eminence seen on the afternoon of proestrus is related to this effect, and the subsequent increase in PRL secretion (Fig. 5) results from removal of the DA inhibition at the level of the anterior pituitary. The cell bodies of the brain beta-endorphinergic system are believed to be located exclusively in the arcuate nucleus (Bloom et al., 1978), and the decreased Beta-endorphin content of this nucleus on the afternoon of proestrus may reflect increased axonal transport to the median eminence and the suprachiasmatic nucleus. We are unable to relate the increased Beta-endorphin to any physiological effects. However, it is interesting to recall the importance of this nucleus in the regulation of diurnal rhythms and, presumably, the estrous cycle in view of its acute sensitivity to light/dark cycles. Moreover, a role for endogenous opiate peptides in the regulation of LH secretion has been indicated (Cicero et al., 1979), and recently estrogen-primed ovariectomized rats. It is becoming increasingly clear that peripheral hormones can influence CNS neurotransmitter systems, and the changes in beta-Endorphin seen during the estrous cycle are likely due to fluctuations in peripheral gonadal steroids, particularly estrogens.

114 A Dupont et al

Both estrogens and haloperidol can exert antidopaminergic actions


      1. Substance P as an opioid

Page 50

Other transmitters seem to be involved in this mechanism and interact with endorphins. Substance P has been implicated since this peptide also causes a naloxone-reversible analgesia (Stewart et al., 1976; Frederickson et al., 1978). Enkephalin neurons are closely associated with substance P fibers in the dorsal horn of the spinal cord (Hokfelt et al., 1977b). It has been suggested that since substance P lacks affinity for opiate receptors (Terenius, 1975), the analgesic effect is probably due to activation of enkephalin fibers (Stewart et al., 1976; Hokfelt et al., 1977b). The effect of substance P is rather complex. At high doses, substance P combined with naloxone causes hyperalgesia, thus suggesting that at high doses it stimulates the nociceptive pathway whereas at low doses it causes antinociception through the release of endorphins (Frederickson et al., 1978).


      1. Testosterone and Lutinizing Hormone

In the human male, longterm methadone administration has been reported to depress plasma testosterone levels and impair the function of secondary sex organs (Cicero et al., 1975). In the rat, acute or chronic administration of narcotics has been found to reduce plasma testosterone and luteinizing hormone levels (Cicero et al., 1976a,b).


      1. Prolactin

Prolactin release is increased by the administration of neuroleptics, opiates (Meites et al., 1979), and beta-endorphin and Met-enkephalin (Dupont et al., 1977).


The prolactin-stimulating effect of intravenous methadone is consistent with the previous reports of prolactin increases in man produced by opiates (Tolis et al., 1975; Rolandi and Barreca, 1978; Extein et al., 1979b) and by opioid peptide administration (Lehmann et al., 1979; Stubbs et al., 1978; Foley et al., 1979; Schulz et al., 1980; Pickar et al., 1981). Prolactin secretion is thought to be influenced by several neurotransmitter systems, including inhibitory effects of dopamine and stimulatory effects of serotonin (Boyd and Reichlin, 1978). Naloxone administration has been shown to decrease basal prolactin levels in rats (Bruni et al., 1977) and in man (Rubin et al., 1979), suggesting that the endorphin system may play a role in basal prolactin regulation. Whether this effect is mediated through endorphinergic interactions with dopamine (Snyder, 1978; Tolis et al., 1978;Gold et al., 1978a; Labrie et al., 1979; Guidotti and Grandison, 1979) or through a direct opiate effect on prolactin-secreting cells is unknown (Enjalbert et al., 1979; Bloom et al., 1980).



Acta Endocrinol (Copenh). 1993 Jul;129 Suppl 1:38-40.

The psychogenic effects of prolactin.

Sobrinho LG

Prolactin modulates maternal functions and is involved in behaviour. Binding sites have been identified in the hypothalamus and substantia nigra. Hyperprolactinaemia stimulates dopamine turnover in several areas of the brain, including the nucleus accumbens, and reduces turnover in other regions, e.g. the substantia nigra. Hyperprolactinaemia stimulates the opioidergic system. The portal concentration of dopamine and oxytocin (a prolactin stimulatory substance) may be increased in hyperprolactinaemia. In mammals, prolactin is associated with learning, stimulation of the immune response, reduction of body temperature and increased corticosterone secretion. It is involved in the behavioural aspect of reproduction. Secretion is strongly stimulated in the female rat on exposure to pups. Hyperprolactinaemia in male rats reduces sexual behaviour. Hyperprolactinaemia reduces libido in both men and women but in men it is also associated with low testosterone levels. There is evidence that in families characterized by an absent or alcoholic father young girls may be predisposed to develop hyperprolactinaemia later in life as a reaction to losses. The underlying mechanism of such a psychosomatic reaction, a typical example of which is pseudopregnancy, may be an extemporaneous activation of a neuroendocrine “maternal subroutine” characteristic of pregnancy. Prolactinomas may result from somatic changes occurring in activated lactotrophs.

L.G. Sobrinho,

8 Neuropsychiatry of prolactin: causes and effects,

Baillière’s Clinical Endocrinology and Metabolism,

Volume 5, Issue 1,


Pages 119-142,

ISSN 0950-351X,


Even more than individual survival, reproduction is arguably the most potent driving force of all living creatures. Successful reproduction implies two sequentially related strategies: sexual and parental. Prolactin is a hormone which, in different species and in various ways, appears closely associated with parental functions. Parental strategy depends on a complex system of metabolic and behavioural phenomena; prolactin is one of its important messengers. Abnormalities in prolactin secretion may reflect changes at other levels of the system which in turn may produce further effects. The purpose of this review is to provide information and to promote insight into the relationships between prolactin and psychological (mis)adjustments. Some examples of prolactin-dependent parental functions are given first;


Production of milk or equivalent secretion

Prolactin induces: production, by cutaneous and buccal cells of certain teleosts (cichlids and catfish), of a mucus which young graze upon (Gorbman et al, 1983); secretion of ‘crop milk’, which columbiform birds use to feed their young by regurgitation (Gorbman et al, 1983); increase in the activity of lipoprotein lipase, synthesis of casein, lactalbumin, fatty acids and phospholipids by the breast in all mammals (Cooke, 1989); and secretion of salt (L’Hermite and Judd, 1980), thereby producing milk.

Reduction of anabolic efficiency of peripheral adipose tissue

In rats, prolactin, acting indirectly through an activated mammary gland, reduces lipid deposition in adipose tissue (Flint et al, 1984; Oiler do Nascimento et al, 1989). In rats rendered hyperprolactinaemic by pituitary graft, the antilipolytic action of insulin is markedly reduced, despite the fact that the concentration of insulin receptors in adipose cells increases (Cabrera et al, 1988). In human fat cells, prolactin decreases the affinity of the insulin receptor for insulin (Jarrett et al, 1984), thus contributing to the increased insulin resistance of pregnancy and of pathological hyperprolactinaemia (Gustafson et al, 1980; Pelkonen et al, 1982; Schernthaner et al, 1985).

Feeding behaviour

In some cichlid ‘mouth breeder’ fish, prolactin inhibits the feeding of the parent. In such species, the young dart in and out of the mouth of the protective parents whose feeding responses have been suppressed (Gorbman et al, 1983). Prolactin promotes a major increase in salt appetite in rabbits at the time of parturition and lactation (Friesen and Forsbach, 1981).

Increase in the rate of absorption of nutrients

In rats, prolactin increases the intestinal absorption of fluid and electrolytes (L’Hermite and Judd, 1980), including calcium (Cooke, 1989).

Behavioural, circulatory and cutaneous adjustments to hatching

Prolactin induces broodiness in many birds and develops the naked and richly vascularized brood-spots which provide the appropriate temperature for incubation (Gorbman et al, 1983). In hens (Richard-Yris et al, 1987) and in other species (Buntin, 1986), plasma prolactin rises sharply during the incubation period.

Chemical induction of behaviour in pups

Maternally behaving, lactating rats emit a pheromone from day 16 to day 27 which strongly attracts the young; this pheromone is generated from bile when it enters the caecum. If the secretion of prolactin is inhibited, the composition of the bile is altered and no pheromone is produced (Friesen and Forsbach, 1981). Role of prolactin in parental behaviour Incubating and non-incubating hens display maternal behaviour when exposed to chicks. In the incubating group, the elevated prolactin levels observed during hatching significantly decline by the second day of exposure to the chicks, while the low levels in the non-incubating group do not change (Richard-Yris et al, 1987). In rats, as in hens, prolactin is not necessary for the expression of maternal behaviour (Rosenblatt et al, 1988; see also Pseudopregnancy below). Hypophysectomized, virgin, female rats, confined in a small cage with pups (concaveation), display full maternal behaviour (see Pseudopregnancy). Bromocriptine and other dopamine agonists are unable to prevent this response (Rosenblatt et al, 1988). On the other hand, in hypophysectomized rats, the latency period is significantly shortened by the administration of prolactin (Bridges et al, 1985; Rosenblatt et al, 1988). It is thus clear that the stimulation of the secretion of milk (or equivalent secretion) is only one of the functions by which prolactin participates in the integrated strategy required for the care of the young. Other functions include metabolic and behavioural adaptations necessary to meet the exceptional demands of pregnancy and of lactation. As we ascend in the biological scale, we observe, in higher primates and in man that the role hormones play in sexual and maternal behaviour is relatively minor compared with the role of individual and environmental factors (Keverne, 1988). Nevertheless, some knowledge of the mechanisms operating in ‘lower’ animals may be useful in providing insight into the mechanisms and significance of symptoms of human diseases. Occasionally, these are strikingly reminiscent of once-appropriate behaviours rendered obsolete by phylogenetic, ontogenetic or social evolution.


Prolactin secretion in humans responds briskly to an appropriate external stimulus: the suckling of the infant at her mother’s breast. The stimulation of the breast in non-puerperal women (manually or with a suction pump), or sexual intercourse, induces a remarkable response in a minority (Noel et al, 1974; Stearns et al, 1973). Breast stimulation, but not intercourse, has also been described as producing a prolactin response in a minority of men (Delitala et al, 1987). Prolactin levels also rise following different stimuli such as anaesthesia, major surgery, endoscopic procedures, hypoglycaemia (Noel et al, 1972) and exercise (Delitala et al, 1987). More controversial, but central to this review, is the problem of prolactin responses to psychological stress. Transient prolactin rises have been described in women following medical interviews, gynaecological examinations and endometrial biopsies (Koninckx, 1978), in novice pilots, but not trained pilots, during acrobatic flights (Pinter et al, 1979), and in neurotic, but not in normal women during a mirror-drawing test (Myabo et al, 1977). In young males, Johanssen et al (1983) observed that prolactin concentrations were higher before medical examinations. Prolactin levels were also found to rise in military personnel during a competitive oral examination (Mayerhoff et al, 1988). Reichlin (1988) described the serendipitous observation of a huge prolactin rise (from 40 to 180 ng/ml) in a pregnant woman while arguing with the attending nurse during the course of a metabolic study. Prolactin increases slightly but significantly during ‘spontaneous’ panic attacks (Cameron et al, 1987) and this response is more consistent than those observed for cortisol, growth hormone or catecholamines (catecholamines may even fall). On the other hand, no prolactin response to medical interviews or gynaecologicat examination was observed by Pearce et al (1980). No response was reported by Myabo (1977) to the stressful mirror-drawing tests in normal subjects. The importance of individual factors was emphasized by Naber et al (1984), who found that the prolactin responses to the cold pressor test correlated negatively with the perception of pain, its affective quality and the effort to stand pain. Using another approach, Brooks et al (1986) found that the levels of anxiety in preoperative patients correlated with cortisol and growth hormone, but not prolactin levels. This is at variance with the report by Harper et al (1985), who found a significant correlation between anxiety and prolactin levels in women, but not in men. The findings of these two groups, however, are not nearly as opposed as their conclusions at first appear. The significance values of P were <0.05 and 0.02 in the two experiments by Harper et al (1985), while the non-significant P calculated by Brooks et al (1986) for females was 0.055. As judged by the variability of individual responses or by the scatter of the standard error of the means, it appears that in most studies different psychological stimuli can induce a prolactin response in some individuals. This response is generally, but not always, small, and appears diluted out in the majority of non-responders. While in rats prolactin responds exuberantly to ‘psychological stress’ (Ratner et al, 1989), in humans threatening situations are neither strong nor constant elicitors of a prolactin response.

PROLACTIN ABNORMALITIES IN AFFECTIVE DISORDERS No gross or consistent abnormalities of prolactin secretion are characteristic of any psychiatric disorder (Meltzer and Fang, 1976; Arana et al, 1977; La Fuente and Rosenbaum, 1981). In a controlled study where 24-h prolactin profiles were measured, Halbreich et al (1979) found that a group of seven patients with major depression differed from controls in that they had significantly higher values in the morning and in the evening, a few hours before falling asleep. There was a higher variability in patients than in controls, and there was a tendency for higher 24-h mean prolactin concentrations, which did not reach the level of statistical significance. In a subsequent study in which unipolar and bipolar patients were considered separately, Mendlewicz et al (1980) found that patients with untreated unipolar depression had elevated 24-h prolactin profiles compared with controls, mainly as a result of increased secretion during wakefulness. On the other hand, bipolar patients had abnormally low 24-h profiles due to a lack, or reduction, of the sleep-associated elevation.

PSYCHOLOGICAL COMPONENT IN IDIOPATHIC HYPERPROLACTINAEMIAS AND PROLACTINOMAS Psychological observations There is a wide agreement that patients with hyperprolactinaemia present with an unusual prevalence of depressive disorders.

Fava et al (1981) compared ten women with hyperprolactinaemic amenorrhoea, ten women with amenorrhoea and normal prolactin levels, and ten normal women, matched for age and social class. The hyperprolactinaemic women had significantly higher symptom questionnaire scores on hostility, anxiety and depression than the other two groups. Of these women, 30% met DSM III criteria for a major depressive disorder. Curiously, a group of men studied by the same authors (Fava et al, 1982) did not rate themselves more hostile or depressed than did matched controls, although they had higher indices of anxiety and somatization. Kellner et al (1984) compared 14 hyperprolactinaemic women, 25 non-psychotic patients attending the psychiatric out-patient clinic for anxiety, depression or both, 29 family practice patients and 26 non-patient employees. The groups were similar for age and social class. The Symptom Rating Test and the Symptom Questionnaire were used. The scores of hyperprolactinaemic patients and of psychiatric patients were similar and significantlyhigher than family practice patients and employees, on hostility, depression and anxiety symptoms. Also, the first two groups had lower scores on the ‘friendly’ and ‘relaxed’ subscales. Hyperprolactinaemic women were also found to be ‘more depressive, more aggressive and less self-controlled’ by Keller et al (1985), and to be more depressed and with diminished libido both by Fioretti et al (1978) and by Miiller et al (1979). Rojas et al (1981) reported introversion, depressive and schizoid traits in 10-12 of 15 women with hyperprolactinaemic amenorrhoea using a multiphasic inventory. They found ‘problems of interpersonal relationship, insecurity, difficulty in controlling the instincts and rationalization as a defence to control the impulses’ in 11-13 of these women. Mastrogiacomo et al (1983) compared patients with hyperprolactinaemia with lactating women at their seventh day postpartum. They used semistructured interviews and several questionnaires for physical and emotion of the prolactinoma was reported by Rothchild (1985). Taken together, these observations suggest that hyperprolactinaemia may play a role in the genesis or maintenance of the mood abnormalities. It must be borne in mind, however, that bromocriptine may be an antidepressive with an activity comparable to amitriptyline (Theohar et al, 1982); therefore, the results of therapy with this drug are not necessarily due to its prolactin-lowering effects. Furthermore, the clear-cut difference between hyperprolactinaemic patients and lactating women indicates that the role of prolactin, if any, is not a simple causal one.

Biographical observations

Our group reported that more than half of women with prolactinoma, idiopathic hyperprolactinaemia or normoprolactinaemic galactorrhoea were brought up either without their father, or with an alcoholic, violent father (Nunes et al, 1980; Sobrinho et al, 1983; Sobrinho, 1989). This was significantly different to the findings in a control population of women matched for age and socioeconomic class attending the same endocrine clinic because of a single, benign, non-functioning thyroid nodule (Table 1). Rojas et al (1981) also found that 12/15 women with amenorrhoea/galactorrhoea had been abandoned during infancy. In addition, the father was violent in 8/15 and alcoholic in 6/15. Likewise, Jtirgensen and Bard6 (1983) found that the father had been absent ‘in reality or by devaluation’ in 13/25 women with prolactinoma.

To clarify the nature of the relationship between early paternal deprivation and hyperprolactinaemia we interviewed and performed endocrine studies (at least five morning prolactin levels on different days) on 37 sisters and 17 brothers of patients with prolactinomas. All males had normal protactin levels at all times. The women were compared with 72 controls matched for age and socioeconomic class. It was found that 23 of the 37 sisters and 27 of the 72 controls (a total of 50 women) had been brought up under conditions of paternal deprivation. These women had significantly higher prolactin levels than the others (14.7 ng/ml versus 9.4 ng/ml; P < 0.001). A closer analysis of the data (Figure 1) revealed that most women in the deprived and normal groups had similar, normal, prolactin levels; the differences were due to a significantly higher number of outliers in the deprived group. In this group, 12/50 had average serum prolactins above 20 ng/ml, as opposed to 3/59 of the others. In the 15 outliers, the hyperprolactinaemia was sporadic in five (only one value above 20 ng/ml), intermittent in seven (more than one, but not all, above 20 ng/ml) and persistent in three, one of them with pharmacological responses and a computerized tomographic scan suggestive of a prolactinoma (Sobrinho et al, 1984). Recently, Fava et al (1989) reported that 7/20 women with hyperprolactinaemic amenorrhoea met the DSM III criteria for functional nocturnal enuresis at some time during their childhood. The same was true for only 2/21 women with normoprolactinaemic amenorrhoea, the difference being statistically significant (P< 0.05). In an important number of patients the clinical onset of hyperprolactinaemia closely follows a momentous life event such as marriage, birth of a child or loss of an important person or situation. Besides the description of isolated cases (Sobrinho et al, 1983; Sobrinho, 1989), these associations were also systematically studied by our group (Nunes et al, 1980). A summary of our findings is presented in Table 2. Some such cases were also observed by Jiirgensen and Bard6 (1983), who nevertheless stressed the chronic character of traumatic life-experiences which were always associated with negative self and body images.

Psychoanalytic observations

The psychological observations summarized above demonstrate that hyperprolactinaemia and psychological abnormalities are strongly associated. The nature of this association, however, cannot be clarified by these studies alone. The biographical observations indicate that: (1) women are earmarked early in childhood to develop hyperprolactinaemia later in life; and (2) the clinical onset of the disease is often preceded, and presumably triggered, by some relevant change in the patient’s emotional economy. However, a simple causal relationship cannot be established. In the realm of human psychology one cannot expect a linear sequence, stimulus-sensation-behaviour, the requisite of most animal research. The external stimuli, being processed within the psychobiological framework of the personality, result in highly individualized responses in humans; therefore, a bidimensional methodology for research will have to be considered. A causal/positivistic approach provides reproducible, quantitative evidence of a general kind, while a psychoanalytic/hermeneutic approach is essential to unravel the intricacies of the organization of each personality, and of its interactions with the exterior (Bard6 and Jfirgensen, 1988).

Bearing this bidimensionality in mind, the observations by our group (Nunes et al, 1980; Sobrinho et al, 1978, 1983, 1984; Sobrinho, 1989) and Jtirgensen’s group (Jfirgensen and Bard6, 1983; Jtirgensen, 1988; Bard6 and Jiirgensen, 1988) led to a general conceptualization of the psychological mechanisms operating in people (mainly women) with ‘primary’ hyperprolactinaemia. 1. Most of these patients developed a malignant, symbiotic, relationship with an aggressive, distant or overprotective mother, with poor selfesteem, unable to recognize and promote the process of individuation/ separation of the child. 2. The father, through absence, devaluation or brutality, is unable to repair or support the self-esteem of these mothers, and therefore to reduce their destructiveness. For the same reasons, these fathers are in a poor position to support their children and to provide an alternative model of identification for them. It cannot be overemphasized that ‘the father is, or should be, the first male love and a source of protection and security, who helps the girl to find out the ways of the world, the paths to culture and search of novelty, dealing with both struggle and empathy in the feminine-masculine eternal binomium’ (Cortesfio, 1989). 3. A predominant mechanism of defence of these patients is the splitting off of their ferocious, repressed hostility, leaving (and living with) at the conscious level, an idealized and unrealistic image of a ‘good’ mother. 4. Aggressiveness (which in all individuals fosters creativity as well as violence) is felt as ‘sinful’ and massively repressed. Inherent to this defence is the rigid personality of these patients and the poor quality of their coping strategies: mechanisms of denial develop instead. 5. An important number of these patients live, as adults and in reality, in close symbiotic dependence on their mothers. Some remain virgin and avoid any sexual intimacy. Others maintain sado-masochistic relationships with their partners, as if compulsively repeating their early mother-to-child pattern, in a desperate, always failing and always renewed, attempt to recover an idealized ‘good’ relationship. 6. The sexuality of these patients is, in general, profoundly repressed (Fioretti et al, 1978; MOiler et al, 1979; Sobrinho et al, 1987). The comments by Cortesfio (1989) about one such patient who presented with the persecutory delusion of being accused of homosexuality, summarize a general pattern: ‘ . . . (there are) obstacles in assuming her genitality and heterosexuality. She was unable to construct a feminine identity, nor could she choose a masculine sexual object at the level of the evolution of the Oedipus Complex. Thus, there was a regression to previous stages of the evolution of the Self in which the “homosexual” relationship with her mother and derivatives is not only more possible, but also more necessary, than the “heterosexual” relationship with her father and his derivatives . . . ‘ ; ‘ . . . in this sense “homosexuality” means an attraction to, and a fusion with, her mother which, being aggressive, become prohibited and sinful.’ 7. The ego functions are usually preserved in the sense that overt psychosis is uncommon. However, the efficacy of the above-mentioned defences is limited, as demonstrated by the high prevalence of depression in these patients. A few cases of major psychosis with hyperprolactinaemia have been reported (Clinicopathologic Conference, 1982; Gangbar and Swinson, 1983). Major depression, alcoholism and active psychotic nuclei interfering with the normal function of the Self are not rare and have been described (Jfirgensen and Bard6, 1983; Bard6 and Jfirgensen, 1988; Sousa et al, 1990). 8. The somatic symptoms occasionally appear to derive directly from a failure of the defence mechanisms. This may be the case of men in whom the disease presents as a lifelong process. 9. In many women, however, the onset of the clinical symptoms closely follows either pregnancy, or an external event which might threaten the previous emotional equilibrium. The typical relations of women (and also of men) with prolactinomas do not contain the pleasures of intercourse/challenge/imagination/creativity. They behave as if they have regressed to, or arrested their maturation at, a very early stage of development, in which the well-being appears to depend predominantly on the external stability of their relationships and little on autonomous movements of the Self. Hence, acknowledging significant changes in their equilibrium is unacceptable since they cannot lead to better arrangements (which the patient is not prepared to search for/find) but only to the loss of their more or less satisfactory status quo. The maintenance of this equilibrium is achieved through a massive denial of any potentially disturbing feeling or event. Despite this mechanism, specific demands of the environment may be perceived at a more primitive ‘biological’ level such that a neuroendocrine response is evoked.

Associated symptoms Besides the cardinal symptoms, amenorrhoea and galactorrhoea, patients with hyperprolactinaemia present with an unusual prevalence of symptoms that are not rare in the general population but which can infrequently be explained in terms of their endocrine disturbance. Headaches are significantly more common in patients with hyperprolactinaemia than in a control population (Nunes et al, 1980; Kemman and Jones, 1983; Sobrinho et al, 1983). Certainly, in patients with macroadenomas the symptom can be due to the presence of an intracranial mass. However, for the majority of the patients who have microprolactinomas, or no adenoma at all, it is difficult to accept such a mechanistic explanation. Women with hyperprolactinaemia are overweight compared with agematched controls (Nunes et al, 1980; Sobrinho et al, 1983) and the association with obesity has been repeatedly described (Forbes et al, 1954; Gould et al, 1974; Lachelin et al, 1974; Wallace et al, 1985; Brunet al, 1990). Often, the onset of the menstrual disturbance is accompanied by a period of weight gain (Table 2), a finding also observed by Creemers et al (1990). The role, if any, of prolactin in the genesis of obesity is unclear. In normal women, Wang et al (1987) found a significant positive correlation between prolactin and ponderosity. In hyperprolactinaemic patients there is no correlation between excess weight and prolactin levels (Nunes et al, 1980; Sobrinho et al, 1983; Creemers et al, 1990). Bromocriptine or surgical treatment has been reported to induce a slight loss of weight in patients with macroprolactinomas (Brunet al, 1990; Creemers et al, 1990). Sexual dysfunction is a common finding, as already discussed. The simplistic explanation that the condition is related to the hypo-oestrogenism via genital atrophy and dyspareunia (Jacobs et al, 1976) is difficult to sustain. In a systematic study by our group (Sobrinho et al, 1987), we found that sexual dysfunction was present in 58% of 103 women with hyperprolactinaemia, compared with 27% of 82 controls (P<0.002). Only three of the patients complained of slight intermittent dyspareunia, which was quite distinct from the sexual dysfunction. In the group of patients with amenorrhoea, which included 68 patients, those with and without sexual dysfunction had similar serum oestradiol levels and vaginal cytology. Oestrogen had been taken in the past by 35 of the women without improvement in their sexual dysfunction. Ill-defined symptoms such as lightheadedness and ‘fullness’, with or without objective evidence of idiopathic oedema (diurnal variations in weight), are also more common in hyperprolactinaemic women than in age-matched controls (Nunes et al, 1980; Sobrinho et al, 1983). A case of prolactinoma where bloatedness was a predominant symptom has been reported by Cohen (1982).

Relationship Between Plasma Levels of Prolactin and

the Severity of Negative Symptoms in Patients with


Mehmet Alpay Ates1, Recep Tutuncu1, Ibrahim Oner2, Sarper Ercan2, Cengiz Basoglu3, Ayhan Algul1,

Hakan Balibey1, Osman Metin Ipcioglu4, Mesut Cetin3, Servet Ebrinc3


Relationship between plasma levels of prolactin and the severity of negative

Studies suggest that the relationship between prolactin levels and treatment response may be very important in the treatment of schizophrenic Studies suggest that the relationship between prolactin levels and treatment response may be very important in the treatment of schizophrenic patients. As prolactin increase is related to D2

receptor blockade, prolactin may be a useful

representative marker of the blockade achieved

and thereby—in an indirect manner—of the

efficacy of antipsychotic drug medications. The

results of the studies above suggest that there is a

clear relationship between changes in prolactin

levels and the response to some antipsychotics.

symptoms in patients with schizophrenia

      1. ACTH

The release of adrenocorticotropin and growth hormone is also increased by opiates (Holaday and Loh, 1979).


However, all these are hypothetical, as the initial step of standardizing an assay method for endorphins in body fluids and establishing circadian rhythm, if any, is not completed. In addition, the finding that ACTH and beta-Endorphin originate from the same substance (pro-opiocortin) has led to the speculation that they may be secreted in equimolar proportions and that they share or participate in identical or similar physiological functions. Lending support to such a hypothesis, Guillemin et al. (1977) found that, indeed, ACTH and beta-Endorphin are secreted simultaneously from the pituitary after stress, indicating that the two hormones have an identical regulatory mechanism further confirmation of these findings was provided by Malizia el al. (1979), who noted an increase in the blood levels of both beta-endorphin and ACTH during electroacupuncture. On the other hand, by employing a different approach, Volavka et al. (1979) noted that naloxone administration increased ACTH and cortisol levels in 24 healthy male addicts. This finding indicates the possibility of an inhibitory role of endorphin on ACTH secretion.

As noted above, the current evidence indicates that there may be a relationship between ACTH and beta-Endorphin secretions. However, the nature of this relationship is not firmly elucidated. Furthermore, as circadian rhythms of ACTH secretion are well established, it is imperative to look for similar rhythms for endorphin secretion as well. Therefore, we designed a study to assess the ACTH-endorphin correlations as well as circadian rhythms in normal subjects.





The morning values of ACTH reported here are in agreement with those reported by Krieger et al. (1977, 1979) and fall in the range reported by others (Liotta and Krieger, 1975; Besser and Edwards, 1972; Croughs et al., 1973). The morning plasma beta-endorphin-like immunoreactivity concentrations in our subjects are also in agreement with the values reported by Wardlaw and Frantz (1979) and are slightly lower than those published by Hollt et al. (1979) and Ross et al. (1979). ACTH as well as beta-endorphin levels decreased during the day but the differences were not statistically significant. Evaluating individual fluctuations of

sample (1600 hr). These increases might be a stress response which affects the hypothalamic-pituitary-adrenal axis and manifests itself by the stimulation of the pituitary secretion of ACTH and, in our case, also of beta-Endorphin.





Thus, our results indicate that there is a circadian rhythm for plasma beta-endorphin and that a correlation exists between ACTH and beta-endorphin plasma levels.

The clinical significance of such a finding is uncertain. Guillemin et al. (1977) have noted that both peptides are increased by stress, indicating that endorphin may be related to stress mechanisms.

Plasma endorphin as well as ACTH levels were estimated in normal healthy male subjects. Blood samples were drawn at 0900, 1200, and 1600 hr to determine if there is a circadian rhythm of endorphin secretion. Our results revealed lower endorphin values in the morning blood samples and higher endorphin values in the evening blood samples similar to that of ACTH, thereby indicating a circadian rhythm for plasma beta-Endorphin. A correlation between ACTH and beta-Endorphin plasma levels was also noted.


beta-Endorphin in Human Plasma, Cerebrospinal Fluid, Pituitary, and ACTH-Producing Tumor


It is well known that adrenocorticotropin (ACTH) and beta-endorphin, the 31-amino-acid C-terminal end of beta-lipotropin (beta-LPH), are derived from a common precursor (Mains et al., 1977; Nakanishi et al., 1979). Immunoreactive beta-Endorphin is present in plasma (Suda et al., 1978; Krieger et al., 1979), pituitary (Liotta et al., 1978; Pelletier et al., 1977; Li and Chung, 1976; Li et al., 1976), brain (Krieger et al., 1977a; Rossier et al., 1977), and cerebrospinal fluid (CSF) (Terenius and Wahlstrom, 1975; Shickmanter et al., 1978; Hosobuchi et al., 1979; Akil et al., 1978a).



In contrast, large amounts of beta-Endorphin were present in patients with Cushing’s disease, Addison’s disease and Nelson’s syndrome.




This study shows that beta-LPH is the major opioidlike peptide and that beta-endorphin concentration is extremely low in normal human plasma and pituitary. These data agree with our previous reports (Suda et al., 1978, 1979; Liotta et al., 1978), and support the hypothesis that ACTH and beta-LPH are secreted in the intact form from the anterior pituitary under normal conditions (Scott and Lowry, 1974). The presence of large amounts of beta-endorphin in the pituitaries of the patients with Cushing’s disease could account for the elevated levels of beta-endorphin in the plasma since natural beta-LPH is not converted peripherally to beta-endorphin in vivo in normal subjects (Suda et al., 1978). These levels of plasma beta-LPH and beta-endorphin are just like those found in the pituitary.



The presence of beta-endorphin-like (Akil et al., 1978a; Terenius and Wahlstrom, 1975; Shickmanter et al., 1978; Hosobuchi et al., 1979) and enkephalinlike (Akil et al., 1978b; Same et al., 1978) materials in human CSF has been reported. It has also been reported that IR ACTH and IR beta-endorphin are present in the brain (Guillemin et al., 1962; Krieger et al., 1977a; Rossier et al., 1977); the source of these peptides in the brain and CSF is still unknown. Some reports suggest pituitary origin of these peptides in the brain (Oliver et al., 1977; Moldow and Yalow, 1978), while others suggest brain origin (Krieger et al., 1977b; Liotta et al., 1979; Tramu et al., 1977).

It has also been reported that beta-LPH and beta-Endorphin concentrations were higher in patients with acromegaly than in nonacromegalic patients (Wiedemann et al., 1979); however, they were within normal ranges in two patients with acromegaly in this study.

beta-Endorphin concentration is extremely low in the normal pituitaries, but large amounts of beta-Endorphin are present in the pituitaries of the patients with Cushing’s disease, suggesting in the latter an activated conversion of beta-LPH to beta-Endorphin in the pituitary.

Suppression of IR ACTH and IR beta-LPH concentrations in the surrounding tissues suggests the suppressive effect of hypercortisolemia on the pituitary corticotropin and presumably on the hypothalamic corticotropin-releasing factor (Tyrrell et al., 1978). IR ACTH and IR beta-Endorphin (beta-LPH + beta-endorphin) concentrations were of almost equimolar amounts in the pituitaries of the normal subjects and patients with Cushing’s disease. These data are supported by previous reports of simultaneous release of ACTH and beta-LPH in human plasma



The physiological role of beta-LPH in the human is not known, but the role of beta-Endorphin in states of addiction, psychiatric disease (Ross et al., 1979; Wagemaker and Cade, 1977; Watson et al., 1978), and pain relief (Hosobuchi et al., 1979; Akil et al., 1978a) is one of the most controversial problems at present.

1. beta-LPH is the major opioidlike peptide in normal human plasma and pituitary.

2. Large amounts of beta-Endorphin are present in plasma of patients with endocrine disorders associated with increased ACTH and beta-LPH production, in pituitaries of patients with Cushing’s disease, and in an ectopic ACTH-producing lung cancer.

Finally, it is worth mentioning the speculation by Margules (1979) for the possible existence of an “endoloxonergic system.” It is logical to think of such an endogenous system which will modulate the physiological and behavioural actions of opioids under various conditions. Grivert et al. (1978) observed that an intact pituitary was necessary in order for naloxone to exert the pain-augmenting action of reducing the escape latency of mice on a hot plate. This raised the possibility of the presence of hyperalgesic factor in the pituitary. Intraventricular administration of ACTH 1-24 has been reported to shorten the reaction time in the hot plate test and to reduce the nociception threshold in the tail stimulation test (Bertolini et al., 1979). Amir (1981) further confirmed the hyperalgesic effects of ACTH. It was observed that ACTH in intermediate doses normalized the pain threshold in morphine-treated mice and produced hyperalgesia in drug-naive mice. In addition, ACTH has also been reported to displace beta-endorphin from opiate receptors dose-dependently (Akil et al., 1980). The evidence reviewed here appears sufficient to speculate that ACTH may represent the naturally occurring “endoloxonergic system”, and its simultaneous secretion with beta-endorphin during stress from the common precursor molecule (pro-opicortin), and from the common secretory cells, may enable the former to modulate the physiological effects of the latter.



      1. Lutinizing Hormone

Since luteinizing hormone (LH)-releasing factor (Barry, 1976) and dopamine (McNeil and Sladek, 1978) neurons are aggregated in the same region as beta-endorphin, the interaction of all these neurons may be operative in the regulation of gonadotropin. Opioid substances inhibit LH release in rodents (Bruni et al., 1977) and in adult human male subjects (Stubbs et al., 1978). This inhibitory effect can be competitively abolished by naloxone treatment, thereby indicating the role of beta-Endorphin in the regulation of gonadotropins (Quigley and Yen, 1980).



Similar effect has been confirmed with naltrexone in humans (Mendelson et al., 1978). On the other hand, Quigley and Yen (1980) noted that LH secretion was related to the menstrual cycle. There was no increase in LH in early follicular phase, but a significant LH increase was found during late follicular phase and mid-follicular phase in response to naloxone. During late follicular phase the increase in LH was slow and progressive in contrast to mid-luteal phase, when the increase is prompt and episodic. All these findings indicate an intricate relationship between various factors in gonadotropic control and that naloxone may promote the release of LH by blocking an endogenous opioid ligand that normally inhibits the hypothalamic-pituitary axis.



      1. Vasopressin

Grossman et al. (1980) investigated the opiate control of vasopressin secretion in man with a long-acting analog of Met-enkephalin. Infusion of this drug induced a diuresis that was attenuated by naloxone. Plasma immunoreactive vasopressin failed to increase after administration of the Met-enkephalin analog despite osmotic stimulation with hypertonic saline infusion. Thus, opiates appear to be involved in mechanisms that suppress the osmotically mediated release of vasopressin, but opiate involvement in baroreceptor-mediated release may be quite different.



  1. Exogenous Opioids

    1. Heroin, Morphine, and Methadone in Psychiatric Self medication

There is a vast literature concerning the use of morphine, heroin, or methadone as self-medication for schizophrenic or depressed symptoms (Verebey et al., 1978). Many of these reports are anecdotal or case histories of a single case. However, there are several reports of a fair number of subjects who were doing well on narcotic agonist therapy but developed mental problems when the opioid was withdrawn



1972). These results may not be generalizable to nonaddicts. In opiate addicts the question arises whether the disease preceded the first use of opiate drugs. The administration of beta-endorphin to naive, depressed schizophrenic subjects resulted in reduced symptomatology (Kline et al., 1977; Lehmann et al., 1979). A long-lasting enkephalin analog, Sandoz peptide, has also been administered with general improvement of the state of the patient (Jorgensen et al., 1979; Nedopil and Ruther, 1979).

The common dopaminergic pathways in the striatal, limbic, and hypothalamic areas affected by neuroleptics and opioids in the same way support the use of opioids to relieve some psychotic symptoms. There is no overlap between neuroleptics and opioids in the noradrenergic pathways merging in the locus coeruleus. In this system the opioids act like agonists and produce effects similar to clonidine, the a-adrenergic agonist, in restoring anxious subjects to stable states.


The pilot investigations undertaken in order to evaluate levels of beta-endorphin-like immunoreactivity present in the plasma of heroin addicts revealed a decrease in these as compared to controls, while an increase in levels occurred during the first days of withdrawal. This depression in levels of beta-endorphin-like immunoreactivity is consistent with the reports of Ho et al. (1980). Studies in rats have shown that after long-term treatment with morphine a suppression in hypophyseal synthesis of Beta-endorphin is observed, and, similarly, a reduction in its levels in plasma, although the increase in circulating levels of beta-endorphin-like immunoreactivity elicited by stress remains unimpaired (Ho et al., 1980; Millan et al., 1980; Przewlocki et al., 1979).



Ongoing work with animals has indicated a remarkable similarity between the behavioural effects of beta-Endorphin and methadone hydrochloride (Segal et al., 1979). It is therefore quite possible that substances are involved in the etiology and regulation of affective disorders, we have been investigating the effects of methadone hydrochloride in patients with affective disorder. Patients were less active, appeared less unrealistic, verbalized less feelings of well-being, and showed a reduction in the elation and grandiosity subscales of the Beigel-Murphy Mania Scale. In addition, they appeared more depressed, less humorous and joyful, more distractable, with their speech being more slurred. The patients themselves noted little subjective change.

After methadone, patients were observed to be less depressed, lethargic, and hostile, and showed a decrease in feelings of helplessness-hopelessness and an increase in anxiety. There was a self-rated increase on the tension-anxiety scale.

As expected, methadone caused significant increases in serum prolactin. A number of significant correlation coefficients emerged when prolactin increases were correlated with behavioural and mood changes. There were positive correlations with being clumsy (r = 0.83, p < 0.04), slurring of speech (r = 0.81, p < 0.05), is irritable (r = 0.86, p < 0.03),



and clearheaded (r = 0.85, p < 0.05), and there were negative correlations with an inability to comprehend (r = -0.82, p < 0.05), humorous (r = -0.92, p < 0.02), being distractible (r = -0.85, p < 0.03), jumping from one subject to another (r = —0.92, p < 0.01), showing disorganized speech (r = -0.83, p < 0.04), showing hallucinatory behaviour (r = -0.94, p < 0.01), making grandiose statements (r = —0.88, p < 0.03), and on the thought disturbance scale of the NIMH Rating Scale (r = -0.93, p < 0.01). There were also correlations between mood changes and prolactin responses with negative correlations occurring on the POMS’ vigor (r = —0.93, p < 0.04) and friendliness (r = -0.99, p <

0.02) subscales, and a positive correlation occurring on the fatigue subscales (r = —0.92, p < 0.04). Thus, the increase in prolactin appeared correlated with the ability of methadone to decrease behavioural activation, suggesting prolactin as a marker for methadone’s behavioural effects.

and symptoms in the affective spectrum. Methadone appears to have differential effects in the manics as compared to the depressed patients. In the manics, methadone appears to be sedating, to cause anergia, and possibly to cause dysphoria-depression, whereas in the depressed patients, it appears to have somewhat of an antidepressant effect and to be somewhat activating by enhancing agitation and anxiety.

Our finding that methadone exerts antidepressant effects is consistent with the results of Gerner et al. (1980) and Kline et al. (1977), who have noted antidepressant effects from opiate agonists including beta-endorphin and morphine, and adds support to the hypothesis that opioids may be

our data indicate that methadone affects mood, a simple explanation of how opiates regulate mood is not possible, since methadone both alleviated depression in patients with depression and caused mild anergy and



depression in manics.

As mentioned above, the opiate agonist methadone without question enters the CNS, and has a biological half-life sufficient to be easily studied. Its behavioural effects are essentially identical to those of beta-endorphin in an animal model (Segal et al., 1979).

Here we report preliminary findings from an investigation of the effects of the acute administration of methadone hydrochloride in a group of schizophrenic patients. Six medically healthy, newly admitted acute

Our results showed no significant baseline differences between active and placebo days. Methadone produced a subtle, but definite, rater-evaluated motor slowing, promoted lethargy, deactivation, and blunted affect. “Negative” schizophrenic symptomatology, based upon a withdrawal-retardation factor, was increased (Johnstone et al., 1978; Crow, 1980). Patients appeared less cheerful, talkative, and communicative and seemed more depressed after methadone, and this was confirmed by the patients’ self-ratings, in which there was a mean increase on the POMS’ depression-dejection scale and the fatigue scale.

Consistent with the work of others, serum prolactin rose markedly by 30 min after methadone infusion, and remained elevated throughout the methadone session. The prolactin increases were correlated with changes in behaviour and mood. Negative correlations emerged for the following behaviours: poor judgment (r = -0.83, p < 0.04), distractible (r = —0.99, p < 0.001), jumping from one subject to another (r = -0.91, p < 0.02), anxiety (r = -0.81, p < 0.05), active (r = -0.89, p < 0.023), and the 11-item mania scale (r = -0.90, p < 0.02). The negative correlations with the self-rated mood were: overjoyed (r = -0.93, p < 0.04), cheerful (r = -0.99, p < 0.01), and lonely (r = -0.94, p < 0.03); and a positive correlation for “blue” (r = -0.97, p < 0.02).

Thus, it appears that a methadone-induced opiate receptor activation had a generalized subduing and motor retarding effect in this sample of schizophrenic patients, which generally correlated with the rise in serum prolactin levels. These observations support those of Gerner et al. (1980), who reported six of eight schizophrenics becoming more uncommunicative and withdrawn after beta-Endorphin infusions, but are not supportive of the findings of Kline et al. (1977) and Berger et al. (1980), who described clinical improvement after beta-endorphin infusion. Interestingly, no specific improvements occurred in subscales reflecting schizophrenic thought disorders, hallucinations, or delusions.

In conclusion, preliminary data derived under these experimental conditions suggest that methadone hydrochloride does not exert a specific antipsychotic effect in schizophrenics, but may accentuate emotional withdrawal and depression and decrease motor activity.





3.2. Endocrine Response to Methadone

Intravenous methadone produced a net (methadone change minus placebo change) increase in prolactin and decrease in cortisol in each of the four patients studied. One postmenopausal patient showed a particularly robust prolactin increase; the percent increase from baseline was double that of any other patient.

Oral methadone suppressed urinary free cortisol from an abnormally elevated pretreatment value to extremely low levels during the first week of treatment in the one patient studied (Fig. 5). This suppression continued throughout the drug trial. Following methadone discontinuation, urinary free cortisol increased beyond pretreatment values, suggestive of a rebound phenomenon (Fig. 5).

    1. Ethanol

Alcohol intoxication and opiate poisoning have similar effects, indicating that these two states may be related. Therefore, it appears that some features of alcoholism are mediated via the release of endorphins. Such a speculation is supported by the finding that endogenous morphine-like compounds may be formed in the body from the interaction of dopamine and acetaldehyde (Davis and Walsh, 1970). In fact, Cohen and Collins (1970) have demonstrated the formation of such compounds from catecholamine and acetaldehyde interaction in bovine adrenal tissue in vitro. In addition, naloxone reverses the depressant effects of alcohol in animals and in humans (Moss, 1973), and in animals it inhibits alcohol-induced withdrawal convulsions. Both alcohol and morphine deplete cerebral calcium levels, and reversal of this abnormality by naloxone in rats has led to the possibility that these two drugs even share a common mechanism of action in the CNS.

In patients with surgical emergencies, narcotic administration may be necessary. The opiates may mask the signs and symptoms and the diagnosis of the original pathology becomes extremely difficult. In such cases, naloxone may unmask the symptoms by reversing the opiate effect in 2 to 3 min and thereby assist in making a proper diagnosis.

Based on these findings, Schenk et al. (1978) used naloxone for rousing comatose alcoholics. Similarly, Sorensen and Mattisson (1978) reported the successful reversal of alcohol-induced coma by high-dose naloxone (1-5 mg/kg body wt). On the other hand, Mackenzie (1979) treated successfully a comatose alcoholic with only five doses of 4 mg naloxone each. Jeffcoate et al. (1979) noted that in a double-blind crossover study of 20 volunteers, i.v. injection of 0.4 mg naloxone check prevented the intoxicating effect of alcohol and the impairment of psychomotor performance induced by alcohol. This finding is not surprising in view of the report by Davis and Walsh (1970) that alcohol dependence was analogous to opiate addiction. They suggested that the effects of alcohol may be caused by the generation of endogenous morphinelike alkaloids from the interaction of acetaldehyde and dopamine. In fact, Hamilton et al. (1979) have shown that salsolinol derived from the interaction of dopamine and alcohol has morphinomimetic properties which can be blocked by naloxone. Therefore, the finding by Kimball et al. (1980) that there was increase in opioid peptides in their six subjects is not surprising. Salsolinol in alcoholics may produce intoxication reversible with naloxone but does not have immunoreactivity with endorphin peptides. All these data indicate that naloxone may be useful in the treatment of acute alcoholism and that this promising area needs to be fully explored.



In vitro, high concentrations of ethanol elicited a small (about 20%) stimulation of enkephalin degradation (Table 4) but there was no effect at lower concentrations. Acute and chronic administration of ethanol induced an increase and decrease, respectively, of Met-enkephalin and Beta-endorphin levels in distinct regions of the rat brain. The observed changes suggest that areas with high endorphin levels are more affected than others (Schulz et al., 1980).


The action of depressant drugs such as alcohol and barbiturates in depressing cerebellar cGMP levels (Katz and Catravas, 1976) and that of convulsants in increasing cGMP levels (Suria and Costa, 1973) suggest that a nonspecific common pathway in the cerebellum leads to more or less motor activity.


      1. Tetrahydro Iso Quinolines

Interestingly, salsolinol, an adduct of dopamine and acetaldehyde, reduces contractions elicited by electrical stimulation of the guinea pig ileum, similar to enkephalins, and this action is antagonized by pretreatment with naloxone (Hamilton et. al., 1979).




Another disease entity that may be related to a neuropeptide substrate is that of alcoholism. The close similarities between alcohol and opiate addiction would suggest a common underlying physiological and neurochemical substrate for these two disorders. However, there are as yet no data demonstrating such a common substrate. The possibility that many of the addictive properties of ethanol could be due to the formation of metabolites of CNS neurotransmitters has been studied. For example, Cohen and Collins (1970), as well as Davis and Walsh (1970), suggest that the ethanol metabolite acetaldehyde produces, by a condensation reaction with the catecholamines, tetrahydroisoquinolines, which could be related to ethanol addiction. Moreover, tetrahydroisoquinolines have been located in CNS regions of rats following chronic administration of ethanol (Collins and Bigdeli, 1975).



The role that neuropeptides might play in mediating such a mechanism is obviously, at this time, purely speculative. However, it is well known that endogenous opioids interact with known neurotransmitters in a variety of ways (Hokfelt et al., 1980). For example, it has been demonstrated that the release of various neurotransmitters, including acetylcholine, dopamine, and norepinephrine, is decreased by administration of opiate substances, probably through an alteration of cellular sodium channels (Marwaha and Frank, 1980).

Nevertheless, it is clear that endogenous opioid substances influence a number of well-studied neurotransmitter systems (Bloom, 1979).

The products of acetaldehyde side reactions may influence these neurotransmitter systems in a similar fashion. Recent data support such a hypothesis. Hamilton et al. (1979) recently reported that one of the principal products of the condensation of acetaldehyde and dopamine, i.e., salsolinol, exhibited opiatelike activity on the electrically stimulated guinea pig ileum. Contractions elicited by electrical stimulation of the guinea pig ileum were partially reduced by this tetrahydroisoquinoline compound. This action was antagonized by pretreatment with the narcotic antagonist, naloxone, but was not reversed by naloxone if it had already been initiated. These results thus indicate that the action of salsolinol on the guinea pig ileum resembles, although is not identical to, that of morphine. Such an effect could mean that the chronic effects of ethanol addiction are mediated by similar, or perhaps identical, receptors to those mediating opiate addiction. The recent report that the related neuropeptide, vasopressin, enhances ethanol tolerance (Rigter and Crabbe, 1980) provides additional information suggesting a possible neuropeptide substrate for alcohol addiction.

    1. Neuroleptics

In biochemical terms, too, there is a similarity between neuroleptics and DTyE. Both types of compounds increase dopamine turnover in certain brain areas.



As previously mentioned, the action of DTyE on rat behaviour shows similarities to that of neuroleptics such as haloperidol.

In a pilot study (single-blind), six patients were treated with a daily intramuscular dose of 1.0 mg DTyE/day for 10 days. In a second study, a double-blind crossover design was used in which six patients were given an intramuscular dose of 1.0 mg DTyE/day for 8 days. In the pilot study, neuroleptic medication was discontinued nearly 2 weeks before DTyE injections were started. In the second study, neuroleptic maintenance therapy was continued.

The 6 patients involved in the pilot study all showed marked exacerbation of the psychotic symptoms after discontinuation of neuroleptics. From the fourth day of DTyE medication onwards, three patients showed reduction of psychotic symptoms; the improvement continued from the sixth day through the third week after discontinuation of DTyE. Two of these three patients showed recurrence of psychotic symptoms after the third week (the follow-up of the third patient had to be discontinued when she was transferred to another mental hospital). Therefore, a second DTyE treatment period was started. During this second 4-day period of DTyE medication, psychotic symptoms showed improvement on the third day of treatment for a period of 4 weeks after discontinuation of DTyE treatment. The remaining three patients showed a decrease of psychotic symptoms on day 3 and 4 of medication, but subsequently became psychotic again, with both agitation and aggression.

In the second study, reduction of psychotic symptoms was observed from the first day of DTyE medication. Four of the six patients became psychotic again 4-10 days after discontinuation of treatment, but symptoms were less severe than prior to DTyE medication. The remaining two patients remained free from psychotic symptoms. The same double-blind crossover design was used for two additional patients who—at admission—had not received neuroleptics when DTyE medication was started. Both showed reduction of the psychotic symptoms from the third day of medication. From the sixth day on, both remained free from psychotic symptoms for some months. According to the nursing staff, an improvement of emotional responsiveness was observed in the ward behaviour of all patients. In our third study, involving a total of 10 drug-free schizophrenic patients, DTyE was injected i.m. in a dose of 1 mg daily for 10 days following also a double-blind cross-over design. In 4 of the 10 patients a pronounced antipsychotic effect was observed, in 3 a temporary or slight reduction of psychotic symptoms occurred, and in 3 no response was noted (Verhoeven et al., 1981). No extrapyramidal, cardiovascular, or gastrointestinal side effects were observed.

These results indicate the possibility of an antipsychotic effect of DTyE. In a number of patients psychotic symptoms diminished or disappeared, either briefly (2-3 days) or for a longer time (up to a few weeks to a month after discontinuation of DTyE treatment). Also others have reported some beneficial effects of DTyE in a number of schizophrenic patients (Emrich et al., 1980, 1981; Manchanda and Hirsch, 1981; Tam-minga et al., 1981; Bourgeois et al., 1980). Like y-endorphin, DTyE has recently been demonstrated in human CSF (Loeber et al., 1979).



Evidence in support of this hypothesis has been the demonstration, at least in animals, that DTaE has in several aspects amphetamine-like properties (van Ree et al., 1980). Such central stimulants are known to induce psychoses of the schizophrenic type or exacerbate existing psychoses.

Therapeutic effects have been obtained with beta-endorphin, FK 33-824 (a synthetic Met-enkephalin derivative), and DTyE (a fragment of y-endorphin). It is possible that DTyE, or a closely related peptide, is an endogenous “antipsychotic” and that a DTyE deficiency as a result of disturbed endorphin metabolism contributes to the pathogenesis of (certain types of) schizophrenia.



A full discussion of aminergic theories of euphoria and mania (Bunney et al., 1972; Mandell and Knapp, 1975a; Mandell and Knapp, 1975b) and possible relation to the neuromodulatory influences of the endorphins (Taube et al., 1976) is pertinent but beyond the scope of this chapter. However, a brief discussion of the suggestion that dopaminergic mechanisms might play an important role in mania is required because of the clinical effects of L-Dopa in manic-depressive patients (Bunney et al., 1972; Murphy et al., 1973), known actions of d-amphetamine and opioid agonists at dopaminergic synapses (Carroll and Sharp, 1972; DiChiara et al., 1972; Eidelberg, 1976; Eidelberg and Espamer, 1975; Gessa et al., 1973; Gessa and Tagliamonte, 1975; Puri and Lai, 1974; Snyder et al., 1974), and data that dopamine receptor-blocking antipsychotic agents are antimanic (Gerner et al., 1976).



Haloperidol and pimozide action as antimanic and known dopamine receptor-blocking agents seemingly supports a dopamine hypothesis (Gerner et al., 1976). However, Creese et al. (1976) have demonstrated the substantial affinity of some butyrophenones for the opiate receptor in brain. This observation provides a biochemical rationale for the known influences of these drugs on opiate addiction in animals and abstinence in man (Karkalas and Lal, 1973; Gold and Pottash, 1980; Gold and Kleber, 1979; Van der Wende and Spoerlein, 1973). In fact, the butyrophenones used clinically are analogs of the opiate meperidine (Janssen, 1965). Some of the more potent butyrophenones examined for opiate receptor binding activity were found to have a greater affinity for the receptor than opiates like meperidine and propoxyphene. Benperidol and pimozide were the most active of these drugs and have a binding profile similar to opiate antagonists (Creese et al., 1976; Pert and Snyder, 1974). Haloperidol produces some behavioural effects (e.g., catalepsy) that mimic some of the effects of opiate agonists. Haloperidol can potentiate analgesia and the development of tolerance and dependence to morphine when both drugs are given concurrently (Eidelberg and Espamer, 1975), and produces some degree of cross tolerance with morphine (Eidelberg and Espamer, 1975; Puri and Lal, 1974) Haloperidol also antagonizes morphine-induced hyperactivity very effectively (Carroll and Sharp, 1972; Lai, 1975). These data suggest that opiate receptor activity might be responsible for at least part of the butyrophenones’ antimanic and antieuphoric effects.

The discovery of opiate receptors and endogenous opioid peptides (endorphins) in the brain and the endorphin hypothesis for affective illness have kindled interest in the possible role of endorphin systems in psychiatric disorders (Gold et al., 1977, 1978a, 1979a; Tolis et al., 1978; von Graffenried et al., 1978;Gold and Byck, 1978; Kline et al., 1977; Janowsky et al., 1978).

    1. Nitric Oxide

Mice were exposed for 10–20 min to room air, 100% oxygen (O2) or increasing concentrations of nitrous oxide (N2O) in O2, then tested for 3 min in a staircase inside a glovebag. N2O produced a concentration-dependent increase in the number of steps ascended (NSA) but no change in the number of rears (NR). Pretreatment with naloxone reversed the increase in NSA and also unmasked N2O reduction in NR. By comparison, increasing doses of the narcotic standard morphine reduced NSA and NR; these changes in NSA and NR were sensitive to antagonism by naloxone. The benzodiazepine standard diazepam produced a dose-related reduction in NR while reducing NSA only at higher doses. These data indicate that N2O influences on NSA and NR resemble neither morphine nor diazepam. In addition, it appears that the opioid activity of N2O might mask its antianxiety activity in this particular paradigm.

Nitrous oxide (N20) has long been recognized as a drug with multiple drug effects and practical applications. Clinically, it can reduce patient anxiety as can benzodiazepine drugs and it can also alleviate patient pain in much the same manner as narcotic analgesic drugs (Langa 1976; Barber et al. 1979; Allen 1979, 1984). Herein we report research findings comparing effects of N20 with those of the narcotic and benzodiazepine standards morphine and diazepam, respectively, in the mouse staircase test, which is sensitive to detection of the antianxiety activities of a broad range of clinical anxiolytic drugs (Simiand et al. 1984).

N20 has been widely used to supplement general anesthesia in surgical operations and to produce conscious sedation in clinical dentistry. There is growing evidence that N 2 0 may be an effective anti-stress agent (Steinberg 1954; Russell and Steinberg 1955; Gillman et al. 1982) beneficial in various stressful clinical conditions for which anxiolytic drugs (i.e., benzodiazepines) have been routinely indicated; these situations include dental surgery (Langa et al. 1976), asthma (Smolinskii 1960) and alcoholic withdrawal (Gillman and Lichtigfeld 1981, 1982). N20 has also been demonstrated to exert a specific analgesic effect. Earlier studies have shown that the analgesic effect of N20 can be at least partially reduced by narcotic anatagonist drugs (Berkowitz et al. 1976, 1977). Berkowitz et al. (1979) have suggested that N20 might stimulate neuronal release of endogenous opioid peptides which in turn activate brain opiate receptors. Consistent with this hypothesized mechanism of action, we recently reported that N 2 0 can increase the content of methionine-enkephalin-likeimmunoreactivity in artificial cerebrospinal fluid taken from anesthetized, ventricular-cisternally-perfused rats (Quock et al. 1985). It is also possible that N 2 0 may possess some direct influence upon opiate receptors (Gillman 1984.). It was of interest to determine whether N 2 0 would mimic the behavioral effects of morphine (with which it shares an opioid mechanism of action) and/or diazepam (with which it shares clinical antianxiety drug activity). According to the staircase test, NSA reflects the locomotor activity of the animal, while N R is an index of the emotionality or anxiety state of the animal (Thiebot et al. 1973, 1976). Benzodiazepines and atypical anxiolytic agents reduce N R at doses that exert no influence or produce only a minimal change in NSA. At higher doses, though, both N R and N S A will be suppressed. By comparison, non-anxiolytic agents like neuroleptics and tricyclic antidepressants reduce both N R and N S A in more-or-less parallel fashion. Our data show that N 2 0 can produce a concentrationrelated increase in NSA. If N S A is indeed a reflection of locomotor activity, these findings confirm the earlier work of Hynes and Berkowitz (1979, 1983), who first reported stimulation of mouse locomotor activity by N 2 0 via an opioid mechanism. This increase in N S A was sensitive to antagonism by naloxone. This is in contrast to morphine, which reduced rather than elevate NSA, a finding that duplicates that of Simiand et al. (1984). The locomotor suppressant effect of morphine was also blocked by naloxone. The locomotor effect of N 2 0 is also unlike that of diazepam, which, like morphine, reduced N S A at higher doses. Both diazepam and morphine were capable of reducing N R ; these findings confirm those of Simiand et al. (1984). Our findings also indicate that, unlike diazepam and morphine, N 2 0 failed to suppress NR, even at a concentration of 75%. Higher concentrations of N 2 0 are not testable because of anoxia. However, it is equally clear that our findings are inconsistent with the accepted clinical observations of NzO-induced anxiety-relieving conscious sedation in human subjects (Langa 1976; Barber et al. 1979; Allen 1979, 1984). On the other hand, the findings are quite clear that in naloxone-pretreated mice, N 2 0 can reduce N R in concentration-related fashion. This diminution of N R is, according to the staircase model (Thiebot et al. 1973, 1976), indicative of an anti-anxiety drug effect. Yet this influence of N 2 0 was not manifested until opiate receptors were blocked by naloxone. It would appear that the opioid activity of N 2 0 might mask demonstration of its anti-anxiety activity in this particular paradigm. This would imply that the anti-anxiety activity of NzO might be independent of opioid mechanisms.

Psychopharmacology July 1987, Volume 92, Issue 3, pp 324–326 | Cite as

Comparison of nitrous oxide, morphine and diazepam effects in the mouse staircase test

  1. Opiate Influences on Behaviour

The most basic form of behavioral modulation that occurs probably involves alterations in the daily activities of the organism such as general activity level, eating and drinking, etc. The first study in the literature to observe any form of behavioral effect after systemic injection of opioid peptides was that of Plotnikoff et al. (1976).


endorphins have been implicated in memory, overeating, sexual activity, and some types of mental diseases.


Clearly, at this stage little definitive can be stated with regard to the final place that will be occupied by opioid-PG interactions in the area of mental illness. However, there are enough provocative observations to ensure that this will be a major field of research.CHAPTER 4

Experiments with central administration of beta-endorphin antiserum in which brain-arousal mechanisms were inactivated, as well as experiments with i.c.v. infusion of low doses of beta-Endorphin in which brainactivating system was stimulated, support the notion that this peptide has an important role in inducing wakefulness and possible additional arousal during an increase in brain activity, i.e., during learning (de Wied, 1980; Riley et al., 1980), emotional stimulation, or even stress (Amir et al., 1980).


Such evidence as the behavioral responses induced by endorphin administration (Lehmann et al., 1979) and the relationship of endorphin levels in the cerebrospinal fluid to psychiatric diagnoses (Rimon et al., 1980) has led to the suggestion that endorphins may be linked to psychiatric disorders.


In the rat, graded intraventricular doses of beta-Endorphin produce behavioural effects such as excessive grooming (Gispen et al., 1977), self-injecting behaviour (van Ree et al., 1976), analgesia (van Ree et al., 1978a), catatonic symptoms, and “wet-dog shaking” (Bloom et al., 1976). The behavioural effects of endorphins described above can all be blocked by opiate antagonists.

However, endorphins can also exert an influence on rat behaviour that cannot be blocked with naloxone and is apparently not mediated by opioid receptors in the brain (de Wied et al., 1978a). As compared with the morphinomimetic effect, these behavioural effects can be produced with relatively small doses. Subcutaneous injection of beta-endorphin delayed the extinction of active avoidance behaviour in the rat. This effect was even more marked following treatment with beta-endorphin fragments such as a-endorphin. However, y-endorphin proved to have the opposite effect: it facilitated the extinction of active avoidance behaviour (de Wied et al., 1978a,b). The same disparity of effect between a- and y-endorphin was observed in passive avoidance behaviour: a-endorphin enhanced passive avoidance behaviour, whereas y-endorphin attenuated it. As already pointed out, the morphinomimetic properties of the endorphins disappear when the terminal amino acid tyrosine is split off. de Wied et al. (1978a) found that [des-Tyr1]-y-endorphin (DTyE) lacked morphinomimetic properties but exerted a stronger influence on active and passive avoidance behaviour than did y-endorphin. The spectrum of activity of y-endorphin, and especially of DTyE, showed similarities to that of known neuroleptics such as haloperidol. Apart from its effect on avoidance behaviour, DTyE has other properties in common with conventional neuroleptics such as a positive grasping response.



The discovery that human brain contains peptides with opioid activity has created a worldwide research effort. Since opiate alkaloids have a profound influence on pain, mood, and behaviour in man, the hypothesis has arisen that certain mental disorders could be connected with a dysfunction of the endorphin systems.


Cerebrospinal Fluid Content of Endorphins in Schizophrenia





behavioural Effects of Beta-Endorphin in Depression and Schizophrenia



… ‘

The existence of specific opiate receptors in primate brain and pituitary (Kuhar et al., 1973) and of endogenous peptide ligands for these receptors (Goldstein, 1976; Wilkes et al., 1980) suggests that these endogenous opiates (endorphins) may have a role in regulating human behaviour. In addition to possible involvement in nociception (Hosobuchi and Li, 1978; Oyama et al., 1980; von Knorring et al., 1979), a role of the endorphins in mental illness has been a focus of scientific interest. There are several reasons that suggest such a role: (1) endorphins and opiate receptors are found in brain areas thought to be important in regulating behaviour (Watson et al., 1979); (2) there is an interaction of endorphins with neurotransmitter systems, especially dopamine (Van Loon and Kim, 1978; Watson et al., 1979), thought to be important in mental illness; beta) preliminary animal research has indicated a neurolepticlike effect of endorphins, based on alteration of conditioned avoidance behaviour (de Wied et al., 1978a) and production of catalepsy (Bloom et al., 1976; Jacquet and Marks, 1976); and (4) the common exogenous opiate alkaloids (e.g., morphine, heroin) have psychoactive properties that include production of psychoticlike states or euphoria, as well as a reduction of symptoms in some psychopathologic states (Verebey et al., 1978).



Effects of Opiate Antagonists and Agonists on behavioural and

Neuroendocrine Variables


Several animal and human studies suggest a role for endogenous opioids in the etiology and regulation of affective disorders. In animals, opiate agonists and opioids such as beta-endorphin cause increases in locomotor activity and stereotypy which parallel the effects of psychostimulants, and are possible animal models of mania (Segal et al., 1979).



Endorphin Dysfunction in Panic Anxiety and Primary Affective Illness






While recent studies and hypotheses have suggested a role for opioid peptides in mania, anxiety, psychosis, pain perception, motor behaviour, and neuroendocrine regulation (Gold and Byck, 1978; Gold et al., 1977, 1979a; Kleber and Gold, 1978),


Endorphins and Affective Illness



The discovery of specific opiate receptors (Simon et al., 1973; Pert and Snyder, 1973) and the identification of naturally occurring peptides possessing opiate-like activity (endorphins) (Hughes et al., 1975; Li and Chung, 1976; Li et al., 1976; Bradbury et al., 1976; Chretien et al., 1976) have led to considerable research and speculation regarding the relationship of the endorphin system to psychiatric illness (Usdin et al., 1979; Verebey et al., 1978). The mood-altering and calming effects of exogenous opiates (Jaffe and Martin, 1975), the regional brain distribution of opiate receptors (Goldstein, 1976; Goldstein and Cox, 1977), and the behavioural effects of administered endorphins to rats (Bloom et al., 1976) suggested potential relationships between the endogenous opioid systems and emotional behaviour. Although initial endorphin-behavioural hypotheses focused on etiologic relevance to schizophrenia (Bloom et al., 1976; Segal et al., 1977), alterations in endorphin function have been hypothesized to be reflected in disorders of mood (Byck, 1976; Belluzzi and Stein, 1977; Gold and Byck, 1978).


Ever since the discovery of endorphins, their role in physiological functions and their implications to various illnesses have been explored. Endorphins seem to have a role in pain modulation, obesity, and in the causation of mental illness. 430



A Role for Opioid Peptides in Attentional Functioning

Clinical Implications

In addition, the similarity of opiate effects to the symptoms of several behavioural disorders raises the possibility that these disorders are associated with abnormalities in endorphin production, metabolism, or receptor function. The 20-year search for a role of catecholamines in affective illness and schizophrenia has been recapitulated in 5 short years of endorphin research.

Although simple excesses or deficiencies of endorphins do not seem to be responsible for schizophrenia or affective illness, several studies have pointed to a role of opioid peptides in selected symptoms: hallucinations (Gunne et al., 1977; Watson et al., 1978; Emrich et al., 1977) and unusual thought content (Davis et al., 1977) in schizophrenia and elation and activity level in mania (Janowsky et al., 1978). Several studies have found elevated levels of opiate binding in the CSF of schizophrenic and affectively ill patients (Terenius et al., 1976, 1979), although plasma studies have been less conclusive (Emrich et al., 1979). Opioid peptides may also mediate aspects of pain perception (Buchsbaum et al., 1977) and perhaps account for the pain insensitivity found in affective illness (Davis et al., 1979a) and schizophrenia (Davis et al., 1979b).


    1. Opioids, Feeding and Drinking

Page 63

Another behavior for which endogenous opioids seem to play an important role is regulation of food and water intake. Margules et al. (1978) have shown that elevated levels of endorphin are found in obese rats. Further, intraventricular (i.v.t.) administration of morphine or Beta-endorphin leads to marked increases in feeding (Belluzzi and Stein, 1977; Kenney et al., 1978). M. G. King et al. (1979) evaluated the effects of

A recent experiments by Olson et al. (1980) examined the interaction of several peptides with different levels of sucrose and quinine solutions. The interaction was highly significant. The opiate peptides generally increased fluid intake with the sucrose solutions, increased slightly with the control solution, and had no effect with the quinine solutions. It is also interesting to note that naloxone and MIF-1 decreased fluid intake in a very similar fashion.


Eating behaviour with consequent obesity appears to be related to endogenous opiates. beta-Endorphin stimulates eating behaviour when administered intraventricularly (Grandison and Guidotti, 1977). In pituitaries of genetically obese mice and rats (Margules et al., 1978), increased quantities of beta-endorphin have been found. In rats fasted for 2 to 3 days, a decline was noted in hypothalamic but not pituitary beta-endorphin with no significant change in pituitary or hypothalamic ACTH (Gambert et al., 1980). These findings provide strong evidence that beta-endorphins in the brain may be involved in eating behavior and satiety. An excess of beta-Endorphin may be the underlying cause of obesity, and during fasting a lowered beta-Endorphin level may serve as a mechanism for enhancing energy conservation. However, it is well established that addicts have poor appetite, which may appear contradictory. The poor appetite in addicts may be the result of low concentration of endogenous opiates resulting from high tissue level of exogenous opiates. Excess of circulating endorphins would lead to chronic tolerence in the enkephalin receptors. In this tolerant state of addiction to endogenous opiates (McCloy and McCloy, 1979a,b), the satiety mechanisms do not operate. If endorphins were to be involved in obesity, naloxone would be the ideal drug to block the opiate receptors and to improve obesity.

Naloxone normalizes food intake in genetically obese rats (Brands et al., 1979). Similarly, spontaneous food intake and weight gain were suppressed when naloxone was administered subcutaneously to normal rats (Garthwaite et al., 1980). Pradalier et al. (1980) support the involvement of endorphins in obesity. They found that the threshold of nociceptive flexion reflex in 28 obese women was significantly lower than in 17 controls. In patients with Prader-Willi syndrome, hyperphagia was reduced by naloxone administration (Kyriakides et al., 1980). Givens et al. (1980) measured the beta-endorphin, beta-lipotropin, androstenedione, and testosterone levels in eight obese, hirsute women. Circulating beta-endorphin and beta-lipotropin levels were significantly elevated above the levels in nonobese control subjects and were positively correlated with body weight. Consequent to the data involving endorphins with obesity, Margules et al. (1978) noted elevated levels of beta-endorphins in pituitaries as well as in the plasma of obese rats; however, the brain level of beta-endorphins was normal. These findings suggest that pituitary beta-endorphin and brain beta-endorphin levels are independently controlled and that the beta-endorphin level in the pituitary is related to obesity. In addition, increased levels of beta-endorphin in the peripheral blood indicate that there may be peripheral sites of action involved in the production of obesity. It is suggested that removal of pituitary or injection of nalorphine (Margules, 1979) decreases food consumption. Opiate receptors have been documented in the ileum and are well characterized pharmacologically (Lord et al., 1977) and biochemically (Creese and Snyder, 1975). Ambinder and Schuster (1979) have reviewed all the evidence of the presence of opiate receptors in the gastrointestinal tract and their possible functions. Opiate receptors are seen in highest concentration in the gastric antral mucosa. A strong argument in favor of a peripheral action of opiates in the gastrointestinal tract is the efficacy of loperamide in the control of diarrhea, as this drug does not cross the blood-brain barrier. The role of these receptors in obesity has been clarified by the abolition of overeating following jejuno-ileal bypass (Mills and Stunkard, 1976). All these findings indicate that opiate receptors in the pituitary and in the gastrointestinal tract may at least in part control eating behavior. As naloxone did produce dramatic reduction in eating, perhaps naloxone may be the panacea for this frequently occurring problem.

A possible mechanism by which beta-endorphin could influence body weight is through modulation of insulin secretion. Hyperinsulinemia is present in genetically obese rodents and in obese humans (Bray and York, 1971; Grey and Kipnis, 1971). beta-Endorphin stimulates insulin secretion from the isolated dog pancreas (Ipp et al., 1978), and circulating glucose stimulates the secretion of an insulin-releasing factor from the pituitary of dogs (Chieri et al., 1976). Therefore, Beta-endorphin may be the substance in the pituitary that is responsible for hyperinsulinemia in obesity (Beloff-Chain et al., 1979). Beta-Endorphin secretion may, thus, influence body size through modulation of insulin response to food.



    1. Opiates in Dementia

dogenous opiate systems in learning and memory, a role that is probably inhibitory. In fact, it might be that senile dementia is a result of increased circulating levels of endogenous opiates.CHAPTER 4



Carr (1981) observed that beta-endorphin released into the brain shortly before death may be responsible for the complex psychological responses described by persons who have recovered from near-fatal illnesses. The limbic lobe is rich in cellular receptors for endogenous opiate peptides and the stress associated with such near-fatal illnesses should definitely trigger the release of beta-endorphin and related peptides. It is quite possible that these high concentrations of endorphins in the limbic cortex may give rise to complex psychological symptoms described as limbic lobe syndrome, consisting of euphoria, involuntary recall of memories, a sense of dissociation from one’s body, and auditory, olfactory, or visual hallucinations. Similarly, depersonalized feelings reported by persons exposed to extremely stressful situation may be related to the release of such opioid peptides.

    1. Opiates in Learning, Memory and Cognition

Kastin et al. (1976b) reported the first test of endogenous peptides in a learning paradigm, all after the use of peripheral injections.

Several forms of avoidance conditioning, including both active and passive paradigms, have been used to investigate the effect of opiate peptides on learning and memory. Rigter et al. (1977) found that enkephalin injected s.c. before the retrieval test would attenuate carbon dioxide-induced amnesia. Moreover, the effect was not naloxone reversible, which gave further support to the concept of dissociated behavioral and opiate effects. Rigter (1978) evaluated the effects of a wide range of doses of Met- and Leu-enkephalin injected s.c. in rats and found that no reliable differences existed on the acquisition trial. However, Met-enkephalin diminished amnesia in a dose-dependent fashion when injected before acquisition, retrieval, or at both times. Leu-enkephalin was not effective if injected only before acquisition but did reverse amnesia if injected only before retrieval or if injected at both times. This work suggested that enkephalins might modulate memory processes, with the locus of effect occurring during retrieval rather than storage.

Other recent studies concerning the role of endogenous opiates in learning and memory suggest that the opiates decrease normal performance. Izquierdo et al. (1980) demonstrated that posttraining i.p. administration of Leu-enkephalin and beta-endorphin produced retrograde amnesia for two different tasks in rats. Rigter et al. (1980) found that i.p. injections of both Leu- and Met-enkephalin impaired acquisition of an active avoidance response.



The first study to demonstrate that systemic injections of an opiate peptide could lead to learning effects was reported by Kastin et al. (1976b). They injected rats i.p. with 80 or 800 u.g/kg of Met-enkephalin or [D-Ala2] -Met-enkephalinamide and tested them in a 12-choice Warden maze. Experimental animals receiving either peptide ran faster and committed fewer errors than did controls. Further, [D-Phe 4]-Met-enkephalin, an analog with virtually no narcotic activity, was equally effective in facilitating performance, thus suggesting that behavioral effects are distinct from traditional opiate effects.


Current evidence points to physiological amnesic role for endogenous opiate peptide systems. This is suggested by the Finding that posttraining administration of naloxone i.v. or into amygdaloid nucleus in rats causes memory facilitation (Jensen et al., 1978; Gallagher and Kapp, 1978), whereas injection of opiate agonists as well as beta-endorphin causes full retrograde amnesia for the habituation task in rats. Izquierdo and Grau-denz (1980) noted that the posttraining intraperitoneal administration of naloxone facilitated memory consolidation of the habituation of a rearing response to a tone in rats. Although haloperidol did not produce any effect of its own, it antagonized the effect of naloxone, indicating that naloxone causes memory facilitation through the interaction of dopaminergic and endogenous opioid mechanisms.






The pharmacological effects of opiates may not provide a good model for the effects of endorphins. Rather than searching for separate endorphin-dependent functions (e.g., analgesia, sleep, respiration, euphoria), it is possible that these peptides serve a physiological process that underlies all of these seemingly independent behaviours. Specifically, we have suggested that endorphins might mediate an important aspect of attention or arousal and, thus, could influence mood, pain, and cognitive functions (Davis et al., 1979c).

The notion that opioid peptides may mediate some aspects of atten-tional processing is a particularly attractive concept. Attention, which is important to learning and information processing in general, is disrupted in both affective illness and schizophrenia, although different aspects of attention may be involved. Experimental manipulations of attention alter pain appreciation. A shift in selective attention may be necessary for drive reduction, and opioid peptides appear to play a role in drive reduction reward (Belluzzi and Stein, 1977; Stein and Belluzzi, 1978, 1979). Other drives such as appetite (McCloy and McCloy, 1979; Kyriakides et al., 1980; Pradalier et al., 1980), thirst (Holtzman, 1975), and sexual behaviour (Gessa et al., 1979; Gispen et al., 1976) are also influenced by narcotic antagonists and opioid peptides. It is well known that opiate use affects sexual function in man (Mirin et al., 1980). Drive regulation is disrupted in major psychoses.


Gritz et al. (1976), in a study of the physiological and psychological consequences of single doses of naltrexone in ex-addicts, found that naltrexone significantly improved attention as measured by the Cross-out Test. Naloxone given acutely to schizophrenics in a double-blind placebo-controlled study improved attention, as measured by the continuous performance task, although clinical symptoms failed to improve (Lipinski et al., 1979). Thus, antagonists appear to improve attention in both normal and schizophrenic individuals, which implies that opioid peptides interfere with vigilance or attention.




There are no data currently on the question of whether beta-endorphin or other opioid peptides affect attentional functions in man. However, several peptides related to endorphins, such as ACTH4_10 and MSH, do influence attention in man (Miller et al., 1974; Sandman et al., 1975; Kastin et al., 1971; Van Riezen et al., 1977).

Although there are only limited data suggesting attentional effects of peptides,in humans, the animal pharmacology of opioid peptides provides further intriguing support for an attention hypothesis of schizophrenia. Classic human attention and vigilance task paradigms are difficult to adapt to the rat, but it is clear that avoidance behaviours and their extinction require the deployment of attentional mechanisms, de Wied and his colleagues (de Wied et al., 1978a,b) have reported that a- and beta-Endorphin, beta-LPH61_69 and Met-enkephalin delay extinction of avoidance behaviour in animals. In contrast, 7-endorphin and the des-tyrosine modification of 7-endorphin facilitate extinction of avoidance behaviour. It has been suggested by de Wied and colleagues (1978b) that these substances are not merely degradation products of endorphins but are physiologically significant and serve a function that is opposite in direction to those of other opioid peptides.

Like 7-endorphin and [des-Tyr1]-y-endorphin, the narcotic antagonist naltrexone facilitates extinction (de Wied et al., 1978a).

Mednick (1974) speculated that deficits in avoidance extinction found in children at risk for schizophrenia may be related to an excess of ACTH. The link to schizophrenia is also strengthened by the finding that neuroleptics facilitate extinction of avoidance behaviour in rats (de Wied et al., 1978b), as well as specifically improving attentional performance in schizophrenics (Spohn et al., 1977).


We have reported insensitivity to experimental pain in schizophrenic compared to normal individuals both in subjective reports and cortical evoked potential (EP) correlates of insensitivity (Davis et al., 1979b). This report confirmed earlier findings of insensitivity to clinical and experimental pain in schizophrenics (Malmo and Shagass, 1949; Malmo et al., 1951; Hall and Stride, 1954; Marchand, 1955; Marchand et al., 1969; Sappington, 1973).



It is interesting that the measure of insensitivity that best discriminates normals from schizophrenics is a measure of perceptual accuracy. This measure, termed “percent error,” is an analog of signal detection d’ (see Davis et al., 1979d, for a description). Changes in percent error in schizophrenics may reflect increased moment-to-moment variation in the criterion used to dichotomize the stimuli, rather than changes in perceptual sensitization as proposed in signal detection theory. This could occur if the subject is inattentive, uncooperative, confused, or careless. Perceptual variability in schizophrenics is well known and has been reported for psychophysical as well as EP variables (for a review, see Buchsbaum, 1977). This provides an interesting alternative explanation for the possible therapeutic effects of opiate antagonists in schizophrenia and an attentional improvement in normals (Gritz et al., 1976)—that is, a general reduction in perceptual variability.

If pain insensitivity in schizophrenia is related to an excess of opioid peptides, then naltrexone might be expected to increase sensitivity. To provide preliminary data on this question, naltrexone was administered in a double-blind placebo-controlled pilot study (Davis et al., 1979d) to five schizophrenic patients. Compared to placebo, naltrexone was associated with increased pain sensitivity, measured both by subjective reports and EP correlates of insensitivity. Again, the percent error measure demonstrated this change, suggesting that the pain sensitization was associated with attentional improvement in the naltrexone-treated group.

of the subject’s attention to the stimulus (Hillyard et al., 1978). Many different types of attentional deficit have been reported in schizophrenics.



Although these data supporting the notion that endorphins may mediate attention are indirect and incomplete, we believe they provide a provocative explanation for the scattered and poorly replicated effects of naloxone, naltrexone, and beta-endorphin on the symptoms of schizophrenia.

normal subjects showed significantly greater enhancement of auditory (N120) amplitude with attentional instructions than did schizophrenics. This was more apparent at low than at high stimulus intensities. Visual EPs showed the same trend. This work has provided further support for previous research demonstrating attentional deficits in schizophrenics.

Our main hypothesis in this brief chapter has been that there is a relationship between attentional deficits and opioid involvement in schizophrenia. This hypothesis receives its best support in the association between individual differences in EP measures of performance and pain sensitivity as measured by percent error. Among normal individuals, the enhancement of auditory EP amplitude with attention was significantly correlated with pain sensitivity (Davis et al., 1980). This was not the case in schizophrenic patients. Furthermore, naltrexone, which increased pain sensitivity, also improved (even normalized) the EP correlate of attention (N120 amplitude) for both the visual and somatosensory modalities in this small schizophrenic sample. Thus, attentional function and pain sensitivity are increased by naltrexone. This EP correlate of selective attention is reduced by morphine (Buchsbaum et al., 1980), and increased by naloxone (Buchsbaum et al., 1977), supporting opioid effects on attention in normals.


A vast array of morphological, physiological, and functional changes accompany adult development into old age (Finch and Hayflick, 1977).



Many of these changes are no doubt related; e.g., changes in neurophysiological and neurochemical substrates may account for many of the functional deficits observed during senescence (Joseph et al., 1978). The widespread distribution of neuropeptide systems in CNS regions that subserve age-related functional declines (Snyder, 1980), suggests that changes in neuropeptide function may be related to these deficits.

1970; Johnson and Erner, 1972). Changes in neuronal dendritic morphology have also been reported (Brizzee et al., 1975), as well as changes in neurotransmitter synthesis, release, and function (Finch, 1974). Age-related changes in postsynaptic receptor density, and affinity have also been reported (Joseph et al., 1978; Roth, 1979).

It is becoming clear, however, that neuropeptide mechanisms may be involved in one of the most often cited functional deficits associated with aging, i.e., the age-related decline in learning and memory function (Jensen et al., 1980). It has been known for some time that operant performance declines with age (Arenberg and Robertson-Tchabo, 1977). Deficits in classical conditioning have also been reported (Hernandez et al., 1979; Buchanan et al., 1979). Moreover, a number of pituitary hormones including ACTH and vasopressin as well as related neuropeptides have been shown to affect learning and memory in both old and young animals (Cooper et al., 1980). Over a decade ago de Wied and his associates reported that ACTH impaired extinction performance, while having no effect on acquisition of conditioned avoidance in rats (de Wied, 1965). Vasopressin also prolongs extinction in a conditioned avoidance task. Moreover, hypophysectomized rats revealed impairments in conditioned avoidance learning while exogenous treatment with vasopressin ameliorated this impairment (Bohus et al., 1973). Studies using the Brattleboro rat, which suffers from hereditary diabetes insipidus and thus lacks the ability to synthesize vasopressin, support these findings. These studies have demonstrated marked memory deficits associated with both active and passive avoidance conditioning in the Brattleboro rat (de Wied et al., 1975). The role that vasopressin and other neuropeptides might play in learning and memory in both old and young rats was recently reviewed (Cooper et al., 1980). These investigators found that treatment with vasopressin improved the performance of old (19 months) rats that showed deficits in both a passive avoidance and a conditioned flavor aversion task. These data strongly suggest that neuropeptide substrates may underlie some of the behavioural deficits associated with old age.



Both ACTH4_10 and vasopressin have been evaluated for possible effects on learning, cognition, and memory in elderly subjects. However, as noted in a recent review (Ferris et al., 1980), these studies reveal that although ACTH analogs appear to affect attention and learning in normal human subjects, studies with elderly subjects, especially those with senile dementia, suggest that these neuropeptides have little clinical efficacy. Although the data are limited, early results suggest that vasopressin may, however, improve cognitive functioning in the elderly (Ferris et al., 1980).

Recent research suggested that the endogenous opioids may also be involved in learning and memory. For example, the administration of naloxone during or after passive avoidance learning has been shown to enhance the later performance of these behaviours by increasing response latency (Rigter et Til., 1977; Messing et al., 1979; Jensen et al., 1978).

Gallagher and Kapp (1978) reported that posttrial intra-amygdaloid administration of naloxone in rats also enhanced memory for a passive avoidance response; moreover, these effects were dose related and time dependent. Classical conditioning tasks are also affected by the administration of naloxone; e.g., extinction performance is prolonged, suggesting a possible effect on memory processes (Izquierdo, 1979; Hernan-dex and Powell, 1980).

Further evidence that endogenous opioids may be related to learning and memory comes from recent findings indicating that naloxone, as well as endogenous opioids, may alter the reinforcing properties of stimulus consequences. For example, endogenous opioids have been demonstrated to initiate and maintain self-administration behaviour in laboratory animals (Stein and Belluzzi, 1979). Rats will also self-administer enkephalins intraventricularly; moreover, naloxone suppresses the rate of intracranial self-stimulation in CNS areas known to be rich in endogenous opioids (Stein and Belluzzi, 1979; Kornetsky and Esposito, 1979). However, whether such effects are related to the manifestations of aging discussed above is unknown.

Other investigators have, however, reported data suggesting such a relationship. The recent report by Jensen et al. (1980) that naloxone treatment produced an enhancement of memory in young rats but impaired retention in aged male rats may suggest an involvement of endogenous opioids in age-related learning and memory deficits. These investigators trained old (26 months) and young (5 months) rats on (1) a passive avoidance task and (2) an operant swimming task. Naloxone was administered either immediately after or 30 min after training. The results showed that naloxone improved performance in both tasks in young animals but impaired performance in the older rats. Moreover, it was determined that naloxone had no effect on either shock sensitivity or reactivity in either age group. Even more interesting is the report by these investigators that there were age-related differences in both opiate receptor binding affinity and density in various brain regions of young and old rats. These age-related receptor changes differed as a function of sex. Thus, the direction of the memory-modulating effects of endogenous opioid agonists and antagonists appear to depend on both age and sex.

As noted above, many receptor changes occur in various mammalian organ systems as a function of aging (Roth, 1979).



    1. Opiates and Increased Emotionality

These findings were somewhat comparable to those reported by Veith et al. (1978), which indicated an increased level of emotionality.

Veith, J. L., Sandman, C. A.. Walker. J. M., Coy, D. H.. and Kastin. A. J., 1978, Systemic administration of the endorphins selectively alters open field behavior of rats, Pharmacol. Biochem. Behav. 20:539.


    1. Opiates in addiction

Support for the use of FK 33-824 as a morphine substitute comes from a recent study by Holmstrand and Gunne (1980) in which the analog relieved distress in six of eight addicts undergoing withdrawal. However, the patients reported that they did not like using FK 33-824.CHAPTER 4

Thus, it seems that a relationship exists between a sensation-seeking behaviour and the endorphinergic activity (Johansson et al., 1979).

With respect to the personality traits, extraversion and neuroticism as estimated by means of the Eysenck Personality Inventory, no straightforward relationships were found. However, in an earlier study by Bond and Pearson (1969), it was suggested that patients with high extraversion and high neuroticism both experienced pain very intensively and had a tendency to communicate this experience freely. Thus, these patients were identified as “complainers” by the staff at the wards and these patients received more analgesic drugs than the patients in the other groups, who either did not experience the pain as intensively or did not communicate their pain experience as freely. When patients were divided into complainers and noncomplainers, it was found that in the complainer group there was a high discrepancy between reported symptoms and observed signs in physician’s rating by means of CPRS (Table 5). Thus, the relevance of the subdivision made by Bond and Pearson (1969) seems confirmed. Furthermore, the complainers had significantly lower pain thresholds and lower tolerance levels. They also had significantly lower concentrations of fraction II endorphins in CSF (Table 5). As concerns fraction I endorphins, there was a tendency toward lower concentrations in the complainer group but there was no significant difference (Table 5).



      1. LSD in alcohol use disorder

The introduction and use of the narcotic namely, the use of drug assisted psychotherapy employing LSD. The treatment form that has been conceptualized as psychedelic (LSD) peak psychotherapy has been applied in the treatment of dysphoric states in alcoholics (Kurland et al., 1967; Unger et al., 1968), cancer patients, and neurotics (Savage et al., 1973), resulting in a decreasing need for opiate drugs in some patients (Pahnke et al., 1970). In this study, the data indicated that verified abstinence throughout the first year was significantly in favor of the experimentally treated addicts as compared with a control group in the program (Savage and McCabe, 1973).



    1. Stress and Opioids

Stress, as will be shown later, has a profound effect on beta-Endorphin levels in hypothalamus.

Clinically, it is well known that lesions that disturb the integrity of the hypothalamus result in a dramatic impairment of consciousness (Ran-son, 1939; French and Magnoun, 1952; Martin et al., 1977)

This finding is of particular importance, since, as will be shown below, brain beta-endorphin seems to respond to stress.



The development of analgesia following exposure of experimental animals to stress has been well established. The stress model may be acute, or more prolonged, and has included inescapable foot-shocks (Akil et al., 1976; Chesher and Chan, 1977; Chance et al., 1978; Lewis et al., 1980), immobilization (Baizman et al., 1979), noise (Katz and Roth, 1979), rotation (Hayes et al., 1976), hot-plate exposure (Amir and Amit, 1979), and intraperitoneal injection of hypertonic saline (Hayes et al., 1976). This stress-induced analgesia shares features of opiate analgesia; it exhibits adaptation to continued stress (similar to tolerance to repeated opiate administration), cross tolerance with morphine, and partial reversal by naloxone (Chesher and Chan, 1977). Further, indirect evidence that stress-induced analgesia may be mediated by an endogenous opioid peptide pain-inhibiting system is the fact that stress decreases beta-endorphin levels in the anterior pituitary (Baizman et al., 1979; Rossier et al., 1979), suggesting that release of this peptide from the pituitary may be a physiological response to stress.



Hypophysectomy results in a gradual decrease in the brain level of beta-endorphin, with the largest decrease in the hypothalamus. Chronic stress in intact animals causes an increase in the brain concentration of beta-endorphin, while brain trauma (concussion) causes a decrease in the level of Beta-endorphin in the hypothalamus.


      1. Shock

In animal studies employing rats, cats, and dogs, naloxone rapidly increased blood pressure and significantly decreased mortality associated with endotoxic, hemorrhagic, and spinal shock. In addition, naloxone was shown to decrease significantly the paralysis resulting from spinal cord injuries in cats. Available data indicate that naloxone produces these effects by antagonizing endogenous opiates (endorphins) secreted from the pituitary gland in response to the stresses of shock of spinal trauma. These investigative developments, if substantiated, may significantly improve survival and functional recovery.



    1. Opioids and Sleep



In low doses (</= 1 ug), beta-endorphin has a generalized arousal effect on CNS; it reduces or even abolishes sleep, while specific beta-endorphin antiserum significantly increases time spent in slow-wave sleep.


  1. Opiate Receptors

As stated earlier, opiate receptor binding is inactivated by reagents that alkylate sulfhydryl groups, such as N-ethylmaleimide (NEM).


Page 61

The discovery of opiate receptors in the brain by Goldstein et al. (1971), Simon et al. (1973), Pert and Snyder (1973), and Terenius (1973) was soon followed by the discovery and sequencing of endogenous opiates by Hughes et al. (1975) and Terenius and Wahlstrom (1975a,b). After the confirmation of the existence of brain opiates, several groups began to focus on the role of these peptides in modulating behavior.


Central Nervous System Effects after Systemic Injection of Opiate Peptides



It is commonly accepted that the opiate drugs and the enkephalins and endorphins exert their effects by binding to stereospecific receptors on membranes. There appear to be several types of receptor and four main varieties have so far been claimed, k, sigma, delta, and mu. (Martin et al., 1976; Lord et al., 1977).


Possible Roles of Prostaglandins in Mediating Opioid Actions


Although some features of opiate binding to cerebroside sulfate mimic those of the opiate receptors (Loh et al., 1978), cerebroside sulfate is clearly not identical with the opiate receptor; whether or not it constitutes a portion of the opiate receptor is not entirely clear.



Four different subreceptors, namely mu, kappa, delta, and sigma receptors. The mu receptors have been identified in the CNS and guinea pig ileum and are strongly sensitive to the pharmacological action of naloxone and mediate morphine analgesia. The endogenous ligands for these receptors are apparently endorphins. The kappa and sigma receptors are located in the CNS and are moderately sensitive to the action of naloxone. The delta receptors have been identified in mouse vas deferens and nerve tumor cells and are moderately sensitive to naloxone but respond well to enkephalin (a natural receptor agonist). In addition, there are excitatory opiate receptors in the CNS that are not blocked by naloxone, and mediate the syndrome of hyperexcitability and explosive motor behavior seen after direct microinjection of morphine into certain CNS sites (Jacquet and Lajtha, 1974).



As previously mentioned, there are four different varieties of opiate receptors: mu-receptor agonists characteristically produce analgesia, euphoria, respiratory depression, and miosis; K-receptor agonists produce euphoria, delusions, and hallucinations (Martin et al., 1976). Morphine is predominantly a mu agonist but with some kappa activity (Martin, 1976); pentazocine, nalorphine, and cyclazocine are partial agonists at the k receptor, and agonists at the a receptor, at the same time being competitive antagonists at the mu receptor (Martin, 1976). Delta Receptors respond to enkephalins (Gilbert and Martin, 1976).

The regional distribution of these receptors is well studied (Martin et al., 1976). The cortex and striatum interestingly have the maximum amount of sigma and minimum of mu Maximum amount of a is located in the same area that has the maximum amount of dopamine, which at present has attracted considerable attention in relation to its neuroregulatory role in the pathogenesis of schizophrenia.



The advent of opioid receptors has led to the discovery of a number of endogenous opioid peptides named endorphins. These opioid peptides and their receptors have been found to be present not only in the CNS but also in various other organs including heart, gastrointestinal tract, and adrenal gland. The isolation of endorphins and the discovery of their receptors have prompted studies to elucidate their functions.

Early studies on the distribution of opioid receptors revealed high concentration of receptors in the rat striatum (Kuhar et al., 1973). High concentrations of enkephalins were also recorded in the neostriatum and globus pallidus (Hong et al., 1977a).


It is observed that opiate agonists with affinity for different receptors (mu, kappa, epsilon) and enkephalins appear to bind equally well and with highest affinity to a common site which is named as “mu1 receptors” (Zhang et al., 1981). These subpopulations of opiate receptors seem to be responsible for analgesia.



    1. Inactivation of Sulfhydryl Groups by N-ethylmaleimide (NEM)

As stated earlier, opiate receptor binding is inactivated by reagents that alkylate sulfhydryl groups, such as N-ethylmaleimide (NEM).


    1. Changes in Opiate Receptors Induced by Sodium

Page 19

2.4. Conformational Changes in Opiate Receptors Induced by Sodium

Earlier in the discussion it was mentioned that in the presence of sodium ions, agonist binding is inhibited and antagonist binding is augmented.

This remarkable discrimination by a small ion between closely related molecules (e.g., morphine and nalorphine, oxymorphone and naloxone) is highly specific in that only sodium and to a lesser extent lithium affect differentially the binding of opiates.

Other than sodium, only lithium exhibited any protective effect, but to a lesser degree. It thus was postulated that the protective effect of sodium against the inactivation of receptors via alkylation of sulfhydryl groups is the result of a conformational change that renders the sulfhydryl group less accessible to NEM and is identical to the conformational change that results in enhanced antagonist and reduced agonist binding.


Pure opiate agonists become 12 to 60 times weaker in the presence of sodium. Mixed agonist-antagonist opiates with potential similar to non-addicting analgesics display a reduction in binding potency of about three to sixfold when sodium is incorporated in the incubation medium. This simple “sodium index” of opiates provides an in vitro means of predicting the extent to which an opiate is an agonist or an antagonist (Snyder, 1977).



    1. Cyclic AMP and Prostaglandin release after receptor activation

Relatively little attention has as yet been paid to what happens after receptor activation. It is usually assumed, although often not explicitly stated, that this activation involves modulation of ion fluxes across the membrane. However, some work suggests that cyclic AMP and prostaglandins may also be involved at the second-messenger level.CHAPTER 4

      1. Opioid Stimulation of PGE1 Biosynthesis

Morphine and enkephalins inhibit the ability of prostaglandin (PG) E1 to stimulate the secretion of fluid by, and the contraction of, intestine from rats and guinea pigs (Jaques, 1977; Coupar, 1978). Morphine also blocks the ability of PGE1 to elevate cyclic AMP levels in rat brain (Collier and Roy, 1974) while a pituitary endorphin inhibited both basal and PGE1 stimulated adenylate cyclase activity in neuroblastoma cells (Goldstein et al., 1977). There are a number of possible explanations for this ability of opioids to inhibit several different PGE1 actions. The most likely ones are; (1) Opioids and PGE1 could have physiologically opposing effects on adenylate cyclase and other systems; (2) opioids could block the effects, of PGE1 by inactivating a PGE1 receptor; (3) opioids could inhibit endogenous PGE1 synthesis, so creating a situation where more exogenous PGE1 was required to achieve a given intracellular PGE1 concentration and to produce a particular effect.

While the first type of interaction cannot be ruled out, for a number of reasons, I suggest that opioids can exert the second and third effects. (1) PGE1 seems to be an agent that, like prolactin and angiotensin but unlike insulin and other hormones, induces rather than suppresses activation of its own receptors (Horrobin, 1980a). That is to say, when PGE1 levels fall, tissues become desensitized rather than hypersensitized to exogenous PGE1; on the other hand, the presence of PGE1 enhances the response of the tissue to further addition of PGE1. Apart from receptor desensitization, if a given intracellular PGE1 concentration is required to produce a particular effect, the less endogenous PGE1 there is, the more exogenous PGE1 will need to be added. (2) Lithium, a known inhibitor of PGE1 biosynthesis (Horrobin, 1979b, 1980a; Manku et al., 1979a), has effects on cyclic AMP similar to those of opioids. It reduces the ability of PGE1 to raise cyclic AMP levels (Murphy et al., 1973; Wang et al., 1974). (3) Beta-Endorphin at 10 ng/ml blocked the ability of prolactin to stimulate the formation of PGE1 in rat blood vessels (Manku et al., 1978; Horrobin, 1980d). (4) The pain-relieving action of morphine in rats can be reversed by intraventricular injection of either PGE1 or cyclic AMP (Ferri et al., 1974). The pain-relieving action of morphine can be imitated and enhanced by lithium, a known inhibitor of PGE1 biosynthesis (Jensen. 1974; Horrobin, 1979b; Manku et al.. 1979a; Diamond et al., 1977).

Thus, there is a good deal of evidence that opioids inhibit the effects of PGE1. There is indirect and limited direct evidence that they may do this in part by inhibiting the synthesis of PGE1. Most of the evidence relates to the effects of opioids on the gut and on pain, suggesting that the predominant receptor involved may be the mu receptor (Lord et al., 1977).

In contrast, there is other evidence to suggest that at other receptors, opioids may have quite a different effect, namely enhancement of PGE1 biosynthesis. Opioids may be epileptogenic as well as analgesic, and different receptors, possibly 8 receptors, are believed to be involved (Frenk and McCarty, 1978). Several epileptogenic compounds such as penicillin and zinc enhance PGE1 biosynthesis (Horrobin, 1978a; Manku et al., 1979a) while the antiepileptic drug, diphenylhydantoin, inhibits PGE1 biosynthesis selectively (Horrobin, 1980b). The facilitation by morphine of self-stimulation in rats is inhibited by lithium (Liebman, 1976) in contrast to the potentiation by lithium of the analgesic effects of morphine. Since lithium can inhibit PGE| formation, the fact that it opposes this action of morphine may indicate that morphine is here enhancing There is considerable evidence that PGE1 may play an important role in nervous system function. Very small amounts injected into the cerebrospinal fluid in animals have profound behavioral effects, including a dramatic catatonia that is similar to that produced by some opioids (Horton, 1964; Horton and Main, 1965). At low concentrations PGE1 can inhibit peripheral neurotransmitter release (Hedqvist, 1977) and it has biphasic actions on conduction velocity and action potential amplitude in peripheral nerve (Horrobin et al., 1977). These basic observations make PGE1 a good candidate for involvement in mental disturbances and there is excellent evidence of its involvement in specific mental disorders: Schizophrenia. Platelets from schizophrenics off treatment fail to increase PGE1 formation from DGLA in response to ADP (Abdulla and Hamadah, 1975) in marked contrast to normal platelets and those from manics or depressives. There is a great deal of other evidence, including insensitivity to pain, suggesting that PGE| formation may be defective in schizophrenics (Horrobin, 1977a, 1978b, 1979a, 1980d; Horrobin et al., 1978). This could perhaps be explained if schizophrenic blood contained an abnormal endorphin or large amounts of a normal endorphin that, like beta-endorphin, can block PGE1 biosynthesis. The existence of an abnormal Leu-endorphin has been reported (Lewis et al., 1979) but others have been unable to repeat the work. Since an endorphin excess would produce a PGE1 deficiency, which would produce an excess of 2 series PGs (Horrobin, 1980a,b) and dopamine supersensitivity, the proponents of the endorphin excess, the PGE1 deficiency, the PG excess (Feldberg, 1976; Mathe et al., 1980), and the dopamine theories of schizophrenia may be “blind men feeling different parts of the same schizophrenic elephant” (Horrobin, 1978b).CHAPTER 4

      1. Alcohol Stimulation of PGE1 Biosynthesis

Alcohol is a potent stimulator of PGE1 biosynthesis (Manku et al., 1979b) and the alcohol flush can be blocked either by the opiate antagonist, naloxone, or by the PG synthesis inhibitor, aspirin (Strakosch et al., 1980). It thus seems possible that the opiate flush may relate to increased PGE1 formation. Manic-depressive psychosis. Abdulla and Hamadah (1975) found that at half-maximal ADP concentrations, platelets from manics produced significantly more PGE1 than normal while those from depressives produced significantly less, though not so little as did schizophrenics. Platelets from normal individuals treated with clinically relevant ethanol concentrations behave like platelets from manics (Manku et al., 1979b) and it may be that the similarities between hypomania and mania and moderate alcohol intoxication have a biochemical basis (HorrThere are many similarities between the effects of alcohol and of opioids and there is some degree of cross tolerance. Opioid antagonists may oppose the effects of alcohol on flushing (Strakosch et al., 1980) and on behavior and consciousness (Blum et al., 1977; Mackenzie, 1979; Jeffcoate et al., 1979; Jeffreys et al., 1980), and it has been suggested that opioid release plays an intermediate role in the effects of alcohol. An alternative hypothesis is that both alcohol and some opiate receptors are capable of stimulating PGE1 biosynthesis. They may therefore share common paths of action and blocking opiate receptors may desensitize tissues to the effects of alcohol.obin and Manku, 1980). CHAPTER 4

    1. Lithium, Mania and Opiates

Lithium inhibits DGLA mobilization (Horrobin, 1979b; Manku et al., 1979a). We have proposed that lithium may be of value in the acute manic phase of a bipolar illness because it reduces PGE1 formation. It may be of little value in the acute depressive phase because PGE1 formation is already low. The switch from the manic to the depressive phase may be partly related to excessive depletion of DGLA during the manic phase leading to an inevitable fall in PGE1 formation. In the long term, lithium may be of value in preventing both manic and depressive episodes because it inhibits the excessive mobilization of DGLA and PGE1 formation in the manic phase, and consequently does not allow the DGLA depletion and reduced PGE1 formation of the depressive phase (Horrobin and Manku, 1980). One candidate for a factor activating PGE1 biosynthesis in manics could be an opioid with a predominant action of enhancing PGE1 formation. There is some evidence that opioid antagonism may reduce manic symptoms (Janowsky et al., 1978).CHAPTER 4

Chronic administration of lithium, the drug frequently used in manic depressive psychosis, induces (after a latency of 2-3 days) a dose- and time-dependent transient increase of enkephalin content in the rat caudate nucleus and globus pallidus. No changes, however, were observed in the frontal cortex, hypothalamus, amygdala, and some other brain areas (Gillin et al., 1978). The mechanism underlying such effects of lithium is not known. Lithium even at 1 mM concentration did not affect the in vitro degradation of enkephalin by human cerebrocortical extracts (Table 4).




The clinical similarity between cocaine- and amphetamine-induced and naturally occurring manic states and their blockade by lithium, link the drug-induced and naturally occurring euphorias. Unfortunately, because of its actions on many physiological systems, it is difficult to approach the neurochemical mechanisms of euphoria or pathological euphoric states by deductions from lithium’s mechanism of action. Gold and Byck (1978) have proposed a hypothesis suggesting that endorphins are inextricably involved with hedonic and anhedonic feelings. They suggested that endorphin binding is modified in drug-induced and naturally occurring euphoric states and may explain the action of lithium in preventing and treating these states (Gold and Byck, 1978).

Opiate agonist and antagonist binding to receptors is markedly influenced by sodium. Except for lithium, whose hydration radius is similar to that of sodium, monovalent cations do not change this affinity (Snyder and Simantov, 1977). Agonists and antagonists compete for the same receptors, but the affinity of these receptors at the physiological extracellular sodium concentration is greater for antagonists than for agonists; increasing the sodium concentration enhances this difference.

If lithium administration produced an increase in the cationic concentration that acted in a manner consistent with opiate binding studies, we could expect increased antagonistic binding and decreased binding of euphorigenic agonist compounds. By this logic, lithium should be antieuphorigenic in endogenous pathological states as well as in exogenous drug-induced states as a result of modification of peptide receptor systems. The demonstrated actions of lithium in the treatment of manic states and naloxone in reversing behavioural effects of both morphine and d-amphetamine (Holtzman, 1974, 1976) are consistent with this hypothesis.



Following an initial unsuccessful lithium trial in the hospital (mood cycles were persistent) the patient was maintained for an extended period of time medication-free. During this period the patient reported periodic constipation and diarrhea, severe enough to require medication and/or nursing intervention. Using this symptomatology as a possible marker for systemic and/or regional bowel opioid activity, self-ratings of bowel function were examined in relationship to mood states.


Endorphins and ACTH

Normal Values; Circadian Rhythms


This began with the search for specific receptors for opiate alkaloids and led to the discovery of these receptors in neuronal tissue (Goldstein et al., 1971). Further steps were to identify these receptors and specify their characteristics, their exclusive presence in vertebrates, their prevalence in the mesolimbic system of brain, their conformational specificity for the binding with agonists, antagonists, and sodium ions, as well as their multiplicity.

    1. Opiate Receptor Blockers

All the above-mentioned findings have confirmed the usefulness of opiate receptor blockers in exploring the role of endorphins in neuroendocrine control through the hypothalamic-pituitary axis.

Opiate receptor blocking agents have played a major part in our understanding of the role of endorphins in the pain mechanism, obesity, schizophrenia, endocrine control, drug addiction, alcoholism, memory, and shock.

All currently isolated endorphins have morphinomimetic properties that can be blocked with specific opiate antagonists such as naloxone. They are able to displace morphinelike substances from their specific binding sites. In this respect, beta-Endorphin is most effective in vivo. The endorphins lose their characteristic opiatelike activity when the terminal amino acid tyrosine is removed (Frederickson, 1977).



The studies with opiate antagonists, while often suggestive of a role for endorphins, need to be replicated and extended in terms of dosage and duration of treatment. All of the studies that directly administered an endorphin to human subjects suffer from one or more serious design flaws, such as absence of double-blind and placebo-control, absence of defined diagnostic criteria for subjects, or contamination by concurrent medication given to subjects.


This impression is reinforced by a survey carried out by Bradford et al. (1976), in which 17 National Institute on Drug Abuse funded studies involving 882 addict patients reported that approximately 65% of the addicts participating in programs in which a narcotic antagonist was administered discontinued treatment within the first 3 months. Similarly, Resnick and Washton (1978) observed that only 2% of the population in their studies were opiate-free for less than 3 months.293

2.1. Effects of Learning

In seeking to account for the low retention rate and the high rate of relapse, the undoing mechanism has been attributed to operant (instrumental) and Pavlovian conditioning resulting from the euphoria and relief experienced from physical and emotional distress provided by the ingestion of an opiate. As such, the opiate experience acts as a powerful reinforcer that establishes and maintains the opiate-using behaviour. Other factors adding to this reinforcing process are the conditioning brought about by the repeated pairings between stimuli in the addict’s everyday environment and withdrawal symptoms that appear in association with daily opiate usage.

The meager results obtained first with cyclazocine, a partial antagonist, and subsequently with the “pure” and more potent antagonists naloxone and naltrexone, raised serious questions concerning the extinction hypothesis (Meyer et al., 1976). Such criticisms were challenged on the basis that merely administering antagonists is not sufficient treatment to eliminate all reinforcers responsible for controlling the drug-seeking behaviour since no provision was made during the maintenance with narcotic antagonists to allow the individual to self-administer opiates not only in a secured environment, i.e., a hospital or clinic setting, but also in the normal drug-taking environment. In essence, there had been no opportunity to extinguish the control over the drug-seeking behaviour exerted by the conditioned reinforcers present in the nonsecured environment.



in physiological and psychological components. The addict’s willingness to be maintained on a narcotic antagonist must also take into account the fact that the narcotic antagonists do nothing “positive” for the individual. There is an absence of any subjective effect in meeting unresolved cognitive and emotional needs. Furthermore, extensive clinical experience indicates that lack of compliance is not unique to narcotic addicts. It is a common problem with medications administered for most chronic conditions where the medication is given to prevent the progression of the disease rather than to alleviate a symptom that would recur if the medication were not taken (Renault, 1978). Investigative experiences with the narcotic antagonists have suggested that inhibiting the drug-taking behaviour of the typical, less motivated addict, if anything, results in a reinforcing avoidance of medication.

The patient’s lack of compliance when placebo and programmatic elements are controlled has raised a number of questions. Must antagonists be administered daily, or can they be effectively utilized on a “crisis-intervention” basis? Does a so-called “pure” antagonist, i.e., naloxone, have any significant side effects, particularly those that might bias outcome in favor of patients not receiving active medication? Are some secondary effects remedial, i.e., might not the best antagonist be one with a slight agonistic property of its own? Responses to these questions, however, have suggested that these issues are of relatively minor significance (Hanlon et al., 1977).

treatment would be most efficacious. Resnick et al. (1970), employing a typologic classification of opiate addicts based upon the patients’ self-ratings of the role opiates played in their daily lives, identified two groups. There are those who employ opiates as a form of “self-medication” to relieve symptoms of chronic emotional stress. These patients usually discontinue their treatment with the antagonist prematurely. In contrast, there are those patients who experience no symptoms of affective discomfort or impaired capacity to function in the absence of opiates. These, tend to remain on their treatment with an antagonist for longer periods. Psychosocial and drug history variables have also been examined relative to treatment outcome. Retention was found to be more likely in patients employed full time or attending school, and involved in a meaningful relationship with a nonaddict mate, or living with family members, than



those without friends and living alone (Parwatikar et al., 1976; Meyer et al., 1976). Nevertheless, none of these observations are powerful enough

commitment to their rehabilitation. Contributing to this disinterest have been: the endemic presence of drugs, an environment in which the social and cultural elements are exerting negative influences, the addict’s pathological lack of self-esteem, and an inability to obtain gratification from work or emotional experiences. Moreover, for many there is also a history of previous unsuccessful treatment.

This objective was first pursued with cyclazocine by employing gradually increasing dosage increments that resulted in an opiate-blocking action extending over a period of 72 hr. Its usefulness, however, was limited because of dysphoric side effects induced by the higher dosage (Resnick et al., 1974). With the advent of naltrexone, it was possible by increasing



The inability of the addict to motivate himself has emphasized the need for obtaining a better understanding of the psychodynamics underlying the addictive and deaddictive mechanisms (Alksne et al., 1967; Brill et al., 1972; Kurland, 1978).

Moreover, these studies indicate that, in general, the return to abstinence is seen as a slow process taking place over a period of several years.


The Use of an Oral Opiate Antagonist in Schizophrenia



Opiate receptor antagonists of the “pure” type include the parenterally administered naloxone and the orally effective naltrexone (Martin et at., 1973; Resnick et al.’, 1974). An early report suggested that the former decreased hallucinations in schizophrenic patients (Gunne et al., 1977). The latter is the subject of this review since it, like naloxone, competes with endorphins for opioid receptor sites (Greenstein et al., 1978). Naltrexone acts for approximately 72 hr (Martin et al., 1973) and seems to be particularly free of side effects and toxicity (Greenstein et al., 1976, 1978; Bradford and Kaim, 1977). This drug is rapidly and completely absorbed with peak plasma levels of parent compound in 1 hr and of active metabolite (beta-naltrexol) in 2 hr without accumulation (Verebey et al., 1976). The use of naltrexone in schizophrenic patients was primarily


      1. Naloxone

The presence of an agonist is required for the antagonist to act. Naloxone per se has been shown to produce very little physiological or behavioral effects of its own (Jasinski et al., 1967).

Page 5

In 1977, Gunne and his associates first examined the therapeutic usefulness of naloxone in chronic schizophrenic subjects and observed a significant reduction in auditory hallucinations. This report was later challenged by other studies that were unable to replicate this finding.

Because naloxone has a short biological half-life, the success of therapy with this antagonist would depend on factors such as the size of the dose, the dosage schedule, and the frequency of administration.

Finally, because of the heterogeneity of the schizophrenic disorder and the involvement of a wide variety of etiological factors, it will not be surprising if opiate antagonists fail to produce beneficial effects in patients whose psychosis is unrelated to opioid dysfunction.

In clinical situations, Janowsky and Judd were unable to observe any antagonism by naloxone of methylphenidate-induced aggravated responses in schizophrenic subjects.

Out of 16 separate studies on the effect of opiate antagonists on schizophrenia (see Gerner et al., 1980), 9 studies reported no change and 7 studies reported diminution of some symptoms, especially auditory hallucinations.


Izquierdo and Graudenz (1980) hypothesized that memory facilitation by naloxone was due to the release of dopaminergic and beta-adrenergic systems from inhibition by endogenous opiate peptide systems, which were thought to be amnesic agents.

One conflicting study (Stein and Belluzzi, 1979) suggested that long-term retention of a passive avoidance task was facilitated by relatively high doses of Met-enkephalin and morphine administered centrally and immediately after training. The results to date seem very exciting but a word of caution is in order. Several studies have not found that the opiate antagonist naloxone has any effect on altering schizophrenic symptoms (e.g., Lipinski et al., 1979)CHAPTER 4

5.3. Therapeutic Effects of Narcotic Antagonists and Agonists in Schizophrenia

The antagonists naloxone and naltrexone have been administered to schizophrenic patients with mixed results: some investigators have found no improvement (Kurland et al., 1976; Volavka et al., 1977), while others have found a reduction in hallucinations (Gunne et al., 1977; Emrich et al., 1979; Watson et al., 1978b; Lehmann et al., 1979). Other improvements such as “improvement in behavior” and improved “thought content” have been found after antagonist therapy (Davis et al., 1977).


Naloxone, in very low doses, can completely prevent the actions of opiate agonists, and hence is called a “pure” antagonist.



Naloxone is a competitive antagonist at mu, k and sigma receptors



In normal humans, naloxone is devoid of pharmacological effects (Jasinski et al., 1967); but recently a number of pharmacological effects have been described in animal experiments (Berkowitz et al., 1976; Cohn et al., 1978; McMillan, 1971; Vocci et al., 1976).

Naloxone is a competitive antagonist at mu, k and sigma receptors

It antagonizes the effects of all types of agonists; but the affinity of naloxone for the sigma receptor is less than for the mu receptor. Therefore, larger doses are required to control the dysphoric and psychotogenic effects’ of sigma-receptor agonists. Naloxone has been reported to partially reverse alcohol (Sorensen and Mattisson, 1978), barbiturate (Moss, 1973), and diazepam (Bell, 1975) intoxications, and thus these depressants have been hypothesized to act through endogenously produced mu and k agonists.

Naloxone has a serum half-life of 1 hr and maximum abstinence syndrome is precipitated by administering a dose of 0.4 mg intravenously (i.v.) (Martin, 1976).

A number of experimental findings suggest that naloxone, a competitive antagonist acting at opiate receptors, may have antipsychotic properties:

1. Like other substances with proven antipsychotic properties, naloxone is reported to inhibit apomorphine-induced stereotyped behavior in the rat (Cox et al., 1976).

2. Naloxone and chlorpromazine given together enhance each other’s rate-decreasing effect on schedule-controlled behavior in the pigeon (McMillan, 1971), which suggests that naloxone also has neurolepticlike effects.

3. Naloxone inhibits d-amphetamine-induced increase in locomotor activity in the rat (Holtzman, 1974).

4. Beta-Endorphin induces in rats a catatonia-like state that is rapidly reversed by naloxone (Bloom et al., 1976).

5. Partial opiate agonists like cyclazocine and nalorphine induce hallucinations and dysphoric reactions that are immediately reversed by naloxone (Jasinski et al., 1967).

6. Spontaneous morphine withdrawal results in intense aggression when dependent rats are grouped during the withdrawal period (Boshka et al., 1966; Lal et al., 1971). This withdrawal aggression is believed to result from a dopaminergic supersensitivity and this aggression can be markedly enhanced by injection of otherwise ineffective doses of apomorphine or amphetamine (Puri and Lal,

1973). Naloxone-precipitated withdrawal did not elicit this aggression (Gianutsos et al., 1975). Moreover, when apomorphine was given together with naloxone, the aggression was significantly reduced from that of apomorphine alone.

7. Terenius et al. (1976) found increased levels of endorphin II (which cochromatographs with Met-enkephalin) in the cerebrospinal fluid (CSF) of four patients with chronic schizophrenia which decreased to normal values upon clinical improvement.



Page 186 – 7

These findings have led to the following hypothesis that schizophrenia is a disorder associated with excess of endorphins in the CNS and that naloxone, being a competitive antagonist at opiate receptors, counteracts this hyperfunction of endogenous opiate peptides. Possibly based on this hypothesis, a number of studies have tested the efficacy of narcotic antagonists like naloxone and naltrexone in controlling hallucinations and other manifestations of schizophrenia (Tables 1 and 2).

Gunne et al. (1977) in a single-blind pilot study reported that i.v. injections of 0.4 mg naloxone abolished auditory hallucinations in four of six chronic schizophrenic patients. Two placebo-controlled doubleblind studies (Volavka et al., 1977; Davis et al., 1977) and two placebo-controlled double-blind crossover studies (Kurland et al., 1977; Janowsky et al., 1977), together involving a total of 41 patients, failed to show any therapeutic value of naloxone. Similarly, three single-blind studies (Mielke and Gallant, 1977; Simpson et al., 1977; Gitlin and Rosenblatt, 1978), involving a total of 14 chronic schizophrenic patients, failed to show any therapeutic value of naltrexone. However, two single-blind studies (Orr and Oppenheimer, 1978; Lehmann et al., 1979), one placebo-controlled double-blind study (Lehmann et al., 1979), and three placebo-controlled double-blind crossover studies (Emrich et al., 1977; Vasavan Nair et al., 1978; Watson et al., 1978), involving a total of 34 chronic and 20 acute schizophrenic subjects, showed varying degrees of therapeutic response to naloxone administration.

As noted in the previously mentioned studies, the therapeutic effects of the narcotic antagonists naloxone and naltrexone have not been consistently demonstrated. The short duration of drug administration or inadequate dosage of the narcotic antagonists may have been responsible for the negative results. Animal studies suggest that high doses (1 mg/kg) of narcotic antagonists are required to occupy a large fraction of the opiate receptors in the CNS (Hollt et al., 1975). Therefore, higher doses of narcotic antagonists in schizophrenic subjects might achieve more favorable therapeutic results. It is interesting to note in this connection that those studies using higher doses (Emrich et al., 1977; Lehmann et al., 1979; Watson et al., 1978) reported favorable results. Since some antipsychotic drugs bind to opiate receptors (Creese et al., 1976), the negative results may have been due to the concurrent administration of neuroleptics or inadequate washout period, both of which may produce a blockade of opiate receptors. The best therapeutic results with naloxone were reported in a group of acute schizophrenic patients who had never been exposed to neuroleptic drugs (Emrich et al., 1977).



However, administration of naloxone alone often leads to an increase in serum LH in normal adult men (Morley et al., 1980) and in animals



Volavka et al. (1979a,b) reported that naltrexone as well as naloxone increase serum concentration of ACTH and cortisol, as well as LH and testosterone, thus indicating a stimulating effect on the hypothalamic-pituitary-adrenal system, as well as the hypothalamic-pituitary-gonadal system, in normal human subjects. Since these results appear to be similar to those found in opiate-withdrawal state (Sloan, 1971; Kokka and George, 1974), it is safe to conclude that the effect on the hypothalamic-pituitary-adrenal axis is due to a narcotic antagonistic action that probably causes a release of ACTH secretion by blocking the inhibitory action of beta-endorphin on ACTH secretion (Volavka et al., 1979b).



Due to specificity, rapidity of onset of action, lack of respiratory depressant action, and rapid excretion with virtually no sedative effect, naloxone has been used in neonates at birth to reverse the effects of narcotic analgesics administered to the mothers during labor. Evans et al. (1976) administered 40 mg naloxone i.v. 1 min after birth to 20 of 44 neonates whose mothers had been given pethidine in labor. These neonates were compared with 20 others whose mothers had had only lumbar epidural block. Alveolar ventilation, alveolar Pco2< and ventilatory rates were measured 10 and 30 min after birth. The untreated neonates of mothers given pethidine showed significant ventilatory depression and the naloxone-treated group was comparable with the epidural group. However, naloxone effects diminished in 30 min, thus requiring repeated administration. Thus, naloxone seems to be an effective antidote for treating opiate-induced-symptoms in neonates of mothers who received opiates during labor. Methadone is often used to treat drug addicts, and overdoses of this drug are becoming frequent among children by accidental ingestion. Methadone levels may remain high in blood for 24 hr. Therefore, naloxone can be specially useful in methadone overdose when administered by slow constant infusion (Waldron et al., 1973).





Blachly (1973) administered naloxone intramuscularly in doses of 0.16 to 0.24 mg to 32 patients who requested methadone maintenance treatment. No response to naloxone was noted in 11 patients (34%) and the rest developed withdrawal signs of varying severity after the naloxone injections. Thus, naloxone within a short period of 15 to 30 min was useful in establishing that one third of the patients were not addicted. Thus, it is clear that not all those who register in methadone clinics are addicted, and without a naloxone test some of these patients may receive methadone unnecessarily with consequent hazard of becoming methadone addicts.

Holaday and Faden (1978) noted that administered naloxone not only reversed endotoxin-induced hypotension, but also prophylactically blocked its occurrence; similarly, reversal of surgical (Finck, 1977), septic (Dirksen et al., 1980; Holaday and Faden, 1978; Tiengo, 1980; Wright et al., 1980), and hypovolemic (Faden and Holaday, 1979) shock have been reported. All these data lend support to the conclusion that endorphins may play a pathophysiological role in shock states and consequently naloxone may be an important therapeutic agent in the treatment and management of a variety of shock syndromes.



Naloxone itself is not a pure opioid receptor blocker, and has additional pharmacological actions.

Gunne et al. (1977) described the effect of naloxone using a dosage of 0.4 mg intravenously in 6 chronic schizophrenic patients in a single blind study. In 4 of the 6 patients a transient reduction of psychotic symptoms, especially auditory hallucinations, was observed. In four double-blind, placebo-controlled studies, 20, 11, 8, and 7 patients with schizophrenic psychoses were given naloxone intravenously (Emrich et al., 1977; Watson et al., 1978; Akil et al., 1978; Lehmann et al., 1979). In the study by Emrich and co-workers, 4.0 mg naloxone was given; in the other three studies, 10.0 mg. In a total of 32 patients in these four studies, the psychotic symptoms (specifically, the auditory hallucinations) showed transient reduction 2-7 hr after the injection. In an additional eight studies, both controlled and uncontrolled, no effects on psychotic symptoms were observed after intravenous injection of naloxone or oral administration of naltrexone in schizophrenic patients (Kurland et al., 1977; Mielke and Gallant, 1,977; Davis et al., 1977; Volavka et al., 1977; Jan-owsky et al., 197.7; Hertz et al., 1978; Simpson et al., 1977; Gitlin and Rosenblatt, 1978).

Reduction of manic symptoms was demonstrated in 16 out of a total of 24 patients involved in two double-blind controlled studies (Janowsky et al., 1978; Judd et al., 1978). In both these studies, 20.0 mg naloxone was given by continuous infusion over 20 min; the maximum effect developed 15-30 min after the infusion and lasted between 1 and 2 hr.

A study of 10 patients with schizophrenic and manic syndromes (part of a World Health Organization project on the therapeutic significance of opiate antagonists in the treatment of psychoses) focused on the effect of naloxone on psychotic symptoms and in particular on auditory hallucinations and manic symptoms (Verhoeven et al., 1979b, 1980). In a double-blind, placebo-controlled design, the patients were given a single injection of 20.0 mg naloxone subcutaneously. Five patients had verifiable acoustic hallucinations in the context of a schizophrenic psychosis, and the other five showed manic symptoms in the context of either a bipolar depression or a (schizophrenic) psychosis. All had previously received neuroleptic medication without complete remission; the neuroleptic maintenance therapy was also continued during the naloxone treatment. The symptoms of the manic patients were scored with the aid of the Brief Psychiatric Rating Scale (Overall and Gorham, 1962) and the Biegel-Murphy Mania Rating Scale (Biegel et al., 1971), while those of the schizophrenic patients were scored with the aid of the Brief Psychiatric Rating Scale and a Hallucination Scale. In all cases, moreover, a checklist of individual symptoms was completed on the basis of a complete Present State Examination Interview (Wing et al., 1975).

This controlled study showed no demonstrable influence of naloxone on any of the psychopathological symptoms scored, and in particular no influence on acoustic hallucinations or manic symptoms.

To summarize the above, out of a total of 132 patients with schizophrenic psychoses who have so far been treated with opiate antagonists in several clinical studies, both controlled and uncontrolled, 36 patients revealed a demonstrable therapeutic effect of naloxone consisting of transient reduction or disappearance of auditory hallucinations. The two controlled clinical studies of Janowsky et al. (1978) and Judd et al. (1978) revealed a transient reduction of manic symptoms in 16 out of a total of 24 patients. One controlled study (Verhoeven et al., 1979b, 1980) produced negative results in 5 manic patients.

From these data, it has become obvious that blockade of opiate receptors with opiate antagonists does not invariably result in reduction of psychotic symptoms. The reasons for this discrepancy could be: (1) diagnostic differences in the patients classified as schizophrenics (van Praag, 1976); (2) differences between dosage and route of administration of opiate antagonists; beta) interactions with different opiate receptors in the CNS (Martin et al., 1976; Lord et al., 1977). Low dosage of naloxone could therefore be a reason for noresponse to this treatment.



Page 247

a SB, single-blind; DB, double-blind.

b Responder means abolishment or reduction of hallucinations after naloxone but not placebo.

The patients were treated with a variety of neuroleptic drugs at commonly used antipsychotic doses. The outpatients had depot neuroleptics exclusively. Anticholinergic drugs were used to control extrapyramidal side effects when necessary. In some experiments when drugs were withdrawn, a minimum of 1 week for oral medication and 6 weeks for depot injections was allowed to elapse before a CSF sample was taken.




Three strategies have been utilized to investigate the relationship of endorphins to human behaviour in health and disease: (1) analysis of the level of endorphins or endorphinlike compounds in body fluids; (2) stimulation of opiate receptors by administration of endorphins; and beta) blockade of opiate receptors by administration of the opiate antagonists, naloxone and naltrexone.

There is evidence using all three research strategies that links endorphins to both affective and schizophrenic disorders. Two double-blind studies employing naloxone i.v. [2 mg in 2 patients (Davis et al., 1977) and 20 mg in 12 patients (Janowsky et al., 1978)] have been shown to mildly reduce manic symptoms for short periods (less than 90 min). Lower chronic doses of naloxone (0.4-0.8 mg s.c. t.i.d. for 6-12 days) failed to alter symptoms in depressed patients (Davis et al., 1977; Terenius et al., 1977).



Furthermore, the opiate-opioid antagonist naloxone has been shown to alleviate opiate, opioid-, and psychostimulant-induced increases in locomotor activity in the rat (Segal et al., 1979; Holtzman, 1974).

Effects of Naloxone on Manic Symptoms

Our initial strategy was to study the effects of the opiate antagonist naloxone on manic symptoms (Janowsky et al., 1979; Judd et al., 1980).

Naloxone was found to exert several principal effects on the overall subject group. Pulse rate decreased significantly. In addition, the subject group, as evaluated by their raters, was slightly more drowsy, lethargic, and less active after naloxone. However, naloxone effects on overall self-rated mood were nonsignificant with the exception of a significant but small naloxone decrease in the “high line.” Pulse rate decreased significantly after naloxone.



As shown in Table 1, the manic patient group showed a significant reduction in manic symptoms as rated on the Beigel-Murphy Mania Rating Scale. A more detailed examination of the data revealed that 4 of the 12 manic patients responded to naloxone with a decrease in manic symptoms, as measured on the Beigel-Murphy Mania Rating Scale, and that the others did not change significantly with naloxone. Overall, these naloxone responders were rated less irritable, angry, restless, tense, hostile, and sarcastic after naloxone infusion, with parallel findings in their own self-report data.

The time course of symptom alleviation in each of those manic patients who responded to naloxone was strikingly similar. The response was fully manifested by 15-30 min postinfusion and returned to baseline levels within 1-2 hr. The manics generally became more symptomatic over time after receiving placebo.

other demographic variables. However, the preinfusion baseline behavioural rating data showed that the naloxone responders were rated at base-



line as being significantly more grandiose, restless, and panicky, making more unrealistic plans, and rating themselves as being “higher” than the nonresponder manics. Normal subjects showed very slight but statistically significant decreases in feelings of well-being and feelings of elation and grandiosity. No obvious effects occurred in the depressives and schizophrenics.

teers. Naloxone may decrease manic symptoms and induce mild anergy/ depression in some manics, especially those who have the most extreme symptoms at baseline. Since most of our patients were receiving lithium and/or antipsychotic drugs, the role of naloxone-psychotropic drug interactions as an influence is certainly possible.

Our finding that naloxone may decrease manic symptoms in a subgroup of manics has some support from the work of Davis et al. (1979), who found a consistent decrease in certain manic symptoms in one manic patient after repeated naloxone administrations. Also, in a study complementary to our work, beta-endorphin was observed to cause a switch into hypomania in several depressed patients (Angst et al., 1979). In contrast,

Thus, we feel that if after using a repeated measures design naloxone is found to consistently alleviate manic symptoms in at least a subgroup of patients, this would suggest that opiatelike endogenous peptides may play a role in the pathophysiology of mania, a finding of considerable theoretical significance. Alternatively, it is possible that our results to

possible pharmacological model of mania. Since Segal et al. (1979) and Holtzman (1974) found a decrease in psychostimulant-induced locomotion in rodents after naloxone administration, we hypothesized that naloxone


Naloxone significantly raised the serum cortisol levels of the overall subject group, and no significant effects on cortisol were found during the placebo condition. In general, the cortisol increase caused by naloxone was twofold greater than that seen either at baseline or following placebo administration. The primary naloxone effect on serum cortisol occurred rapidly and was evident in the 15 and 30 min postinfusion serum samples. None of the diagnostic subgroups manifested significantly different or aberrant cortisol responses to naloxone, nor were there any differences between them.



We divided the bipolar patients into those patients who had responded to naloxone with an attenuation of manic behaviour, and those who had not responded. The manic responders manifested a significantly attenuated cortisol response after naloxone, and the nonresponder manics responded to naloxone with marked increases in serum cortisol. However, an examination of the raw data in the responder manics revealed that there was considerable variability in the cortisol responses to naloxone among this group of patients.

Our results are not consistent with findings in animals that naloxone lowers serum prolactin and growth hormone levels (Tolis et al., 1975; Shaar et al., 1977). The slight increase in serum growth hormone activity is difficult to explain, and could be postulated to occur secondary to naloxone’s very mild agonist properties. However, the suggestion that the manics in whom naloxone exerted behavioural effects showed the greatest growth hormone increases suggests growth hormone may be a possible marker for naloxone’s antimanic effects.



It is possible that endogenous opioids exert effects only at certain times of the day, and that our naloxone infusion, given during the daylight hours, was “out of phase.” Our results indicate that naloxone produced a marked effect on serum cortisol in a wide range of subjects. This effect appears to be a general one since there were no differential effects on the basis of diagnosis or of treatment with psychotropic drugs. Interestingly, there were no systematic differences in predrug levels of cortisol among the diagnostic groups. This may have been due to the small number of depressed patients

Results from this study have provided another indication of the opposite effects of naloxone and opiate drugs, and these results support the recently published work of Volavka et al. (1979). It is possible that the observed cortisol elevation may reflect an oppositional effect to a sustained “lowering” of serum cortisol, due to the action of endogenous opioids.

3.1. Naloxone Studies in Schizophrenics

Initially, we tested the ability of naloxone to antagonize psychotic symptoms in eight floridly symptomatic, schizophrenic patients (Janowsky et al., 1977b). In our study, the effect of low-dose naloxone on hallucinations, delusions, and other schizophrenic symptoms was determined using a double-blind, crossover design with a counterbalanced order of administration. Intravenous naloxone (1.2 mg) on one day and

As shown in Table 3, the overall group of eight schizophrenic patients, analysis of variance of all individual BPRS items and total BPRS scores revealed no significant or near-significant differences between placebo and active naloxone trials. No drug-time or placebo-time order effects were noted. No significant changes occurred in the following BPRS

It could be concluded from the above naloxone studies that the endogenous opiatelike peptides may not be involved in the etiology or the pathophysiology of schizophrenia, a finding supported by the work of Volavka et al. (1977) and partially supported by the work of Davis et al.(1977). However, since studies have generally used acute rather than chronic administration of naloxone, it may be unrealistic to expect that the short-term and acute administration of naloxone could induce observable changes in a population of severely disordered patients.

Furthermore, there are intriguing data from several studies indicating that while naloxone does not exert a dramatic effect on schizophrenic symptoms, certain specific behavioural characteristics of schizophrenia are altered, at least several hours after naloxone infusion. In well-controlled studies, Davis et al. (1977) reported a decline in the BPRS “unusual thought” item in schizophrenics, and Berger et al. (1979) and Watson et al. (1978) noted a late-onset reduction in auditory hallucinations. Therefore, it is possible that only specific aspects of schizophrenic behaviour are responsive to naloxone. Nevertheless, what slight evidence there is indicating a moderation of schizophrenic symptoms by naloxone suggests a late onset of effects, indicating an indirect rather than a direct naloxone effect.




365However, naloxone has been reported to be without effects of its own in a variety of behavioural, neuroendocrine, and neurochemical model systems in mammals (Bird et al., 1976; Bird and Kuhar, 1977; Frederickson and Norris, 1976; Goldstein, 1976; Goldstein et al., 1976; Kokka et al., 1973; Rivier et al., 1977). There are no reports of physiological or behavioural effects of naloxone in primates or humans (Eddy and May, 1973; El-Sobky et al., 1976; Goldstein and Hansteen, 1977; Goldstein and Hilgard, 1975; Grevert and Goldstein, 1977).

      1. Naltrexone

Volavka et al. (1979b) found that naltrexone increased serum testosterone concentration in normal men.





Another single-blind study involved two schizophrenic males and one schizoaffective female (Gitlin and Rosenblatt, 1978). Two of the subjects were maintained on neuroleptic drugs. The dosage was 50-100 mg/ day over 2 weeks. No therapeutic effects were observed. Nausea, vomiting, abdominal pain, sleepiness, headache, chills, restlessness, malaise, and shakiness were reported to have occurred soon after initiating naltrexone therapy in the two chronic schizophrenic patients. The authors speculated on the possibility that these symptoms represent withdrawal phenomena from endogenous endorphins.

The results of the next study suggested that a “subgroup” of hallucinating schizophrenic patients may benefit from naltrexone treatment (Ragheb et al., 1980). In an open-label trial in four male and one female actively hallucinating, newly admitted chronic patients, naltrexone was administered in a dosage range of 100-300 mg/day in divided doses. There



was an initial 1-week placebo washout preceding the 3 weeks of active compound, and no psychotropics were allowed. One patient improved markedly, so the dosage was not increased above 150 mg daily. Another subject was dropped at 200 mg/day due to clinical deterioration, and one more was dropped when all American studies were discontinued due to toxicology concerns. Overall, there were beneficial effects in two patients and a worsening in three. The two responders showed improvement on doses of 100-200 mg/day and within 2 weeks of beginning naltrexone treatment. The factors distinguishing the responders from the nonresponders were a history of hallucinations despite adequate neuroleptic maintenance, appropriate adversive reaction to their hallucinations, and the development of side effects during naltrexone treatment.

Davis and colleagues reported on two patients who received naltrexone (Davis et al.,1979), one of whom was administered 300 mg/day for 25 days and showed improved ratings on the psychological instruments. There was a return toward baseline when naltrexone was discontinued. The other patient was given 200 mg/day for 14 days with no change.

Naltrexone has been administered to 34 schizophrenic patients under single- or double-blind conditions to evaluate the possible role of endorphins in schizophrenia. The results were definitely negative in 30 subjects and inconclusive or positive in four subjects. The patient populations were chronic schizophrenic inpatients or schizophrenia in exacerbation, and the dosage ranged well above that providing blockade of opiate receptors.



Trials have not been replicated using the long-acting, oral opiate antagonist, naltrexone. As Gunne and colleagues reported in that early naloxone study, the number of patients responding to opiate receptor blockade with naloxone was very small. They later reported positive placebo responders as well (Gunne et al., 1979).

Assuming that naltrexone provides adequate abolition of opiate cell and endorphin function, one could assume that an excess of endorphins does not play a direct role in the production of schizophrenic symptomatology or of secondary symptoms such as hallucinations. Another possibility is that there is more than one type of opioid receptor (Jacquet, 1979). The receptor(s) stereospecific for naltrexone may not be operative in mental illness.

The four exceptions showed a decrease in hallucinations and/or a reduction in schizophrenic symptomatology. These may have been nonspecific changes since positive placebo effects were noted in some subjects. The patients were generally a chronically ill, hospitalized population diagnosed by RDC or WHO criteria in most cases.