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humans (Hiller et al. 1973) and in all vertebrates so far studied, but they have not been found in invertebrates (Pert et al. 1974).

PROPERTIES AND DISTRIBUTION
OF OPIATE RECEPTORS

The properties of the opiate binding sites have been studied extensively and their distribution in the brain and spinal cord has been mapped in considerable detail by dissection and in vitro binding measurements (Hiller et al. 1973; Kuhar et al. 1973) as well as by autoradiography (Pert et al. 1975; Atweh and Kuhar 1977a,b,c).

The results of extensive mapping studies can be summarized here only briefly. The highest levels of opiate receptors are found in areas of the limbic system and in the regions that have been implicated in the pathways involved in pain perception. lt has been suggested that the limbic system receptors may be involved in opiate-induced euphoria (or dysphoria) and in the affective aspects of pain perception.

Recently, there has been considerable interest in the question of whether multiple types of opiate receptors exist. Using classical pharmacological approaches Martin and collaborators (Martin et al. 1976; Gilbert and Martin 1976) have suggested the existence of three types of receptors, named n (for morphine), K (for ketocyclazocine), and a for SKF 10,047. Results from Kosterlitz' laboratory also provide evidence for the heterogeneity of opiate receptors (Lord et al. 1977). Thus, the receptors present in the guinea pig ileum seem to have properties distinct from those in the mouse vas deferens. These authors have also reported evidence which suggests that the brain may possess at least two families of receptors differing in their affinity for enkephalins and for exogenous opiates.

DISCOVERY OF ENDOGENOUS OPIOID PEPTIDES

The evidence that the brains of all vertebrates investigated from the hag fish to man contain opiate receptors led investigators to raise the question why such receptors exist in the central nervous system and have survived eons of evolution. A physiological role for opiate receptors that conferred a selective advantage on the organisms seemed probable. None of the known neurotransmitters or neurohormones was found to exhibit high affinity for opiate receptors, which encouraged a number of laboratories to search for new opiatelike substances in extracts of animal brain. This search was successful first in the laboratories of Hughes and Kosterlitz (Hughes 1975) and of Terenius and Wahlstrom (1974). Goldstein and his collaborators (Teschemacher et al. 1975), at about the same time, reported opioid activity in extracts of pituitary glands.

These studies culminated in the identification of the opioid substances in extracts of pig brain by Hughes et al. (1975). They reported that the activity resided in two pentapeptides which they named methionine (Met) and leucine (Leu) enkephalin. This was confirmed by Pasternak et al. (1975) who found the same peptides in extracts of bovine brain. The report of Hughes et al. along with that of the Goldstein group of

the existence of opioid activity in the pituitary gland led Guillemin to examine the extracts of pig hypothalami and pituitary glands. Two polypeptides with opioid activity were found and sequenced (Ling et al. 1976). The proliferation of endogenous peptides with opioid activity caused the author of this paper to suggest the generic term "endorphin" (for endogenous morphinelike substance), which has been widely accepted. The C-terminal fragment was renamed /3-endorphin by Li (1964), while LPH 61-76 and 61-77 were named a-and y-endorphin, respectively, by Guillemin (Rossier et al. 1977). ln this paper l use endorphin as the generic term for endogenous opioid peptides of which the enkephalins are a subgroup.'

Endorphins look (structurally) and behave like opiates, binding to the same brain receptors. All the endorphins, including the enkephalins, exhibit opiatelike activity when injected intraventricularly. This activity includes analgesia, respiratory depression, and a variety of behavioral changes including the production of a rigid catatonia. The pharmacological effects of the enkephalins are very fleeting. The longer chain endorphins are more stable and produce long-lived effects. Thus, analgesia due to /8-endorphin (the most potent of all the endorphins so far found) can last three to four hours.2 All of the responses to endorphins are readily reversed by opiate antagonists, such as naloxone.

Studies on the distribution of/3-endorphin in the laboratories of Guillemin (Rossier et al. 1977) and Watson (Watson et al. 1977) have provided convincing evidence for a distribution that is very different from that of the enkephalins. This has led to the suggestion that the central nervous system has separate enkephalinergic and endorphinergic neuronal systems. /3-endorphin is present in the pituitary, where there is little or no enkephalin, as well as in certain regions of the brain. Brain /3-endorphin seems to originate in a single set of neurons located in the hypothalamus, with axons projecting throughout the brain stem.

PAIN AND ITS MODULATION

Since it was work on the opiate analgesics that led to the discovery of the endorphins and their receptors, it was natural to postulate that they might be involved in pain modulation. The fact that all central nervous system regions implicated in the conduction of pain impulses have high levels of opiate receptors supports this hypothesis. These findings do not prove that endogenous opioids are involved in the pain pathway, but are sufficiently suggestive to encourage further testing of this hypothesis.

Attempts were made to demonstrate the role of the natural opioid system in pain perception by the use of the opiate antagonist naloxone. lt was postulated that, if receptor occupancy by endorphins was

'A consensus, however, has not been reached. A number of prominent investigators preferred to call only the longer peptides endorphins, and the shorter ones (viz., 5 amino acid residue) enkephalins, while using the term "opioid peptide" in the generic sense.

2 A newly described pituitary peptide, dynorphin (Goldstein et al. 1979), is claimed to be even more potent than /3-endorphin.

involved in pain modulation, the administration of an opiate antagonist should lower the threshold or exacerbate perceived pain. Such an effect has been surprisingly difficult to demonstrate conclusively, but at least partial evidence has been developed by several researchers, especially in the case of nondrug-induced analgesia such as that resulting from electrical stimulation, acupuncture, and placebo effect (Jacob et al. 1974; Frederickson et al. 1977; El-Sobky et al. 1976; Grevert and Goldstein 1978; Akil et al. 1976; Hosobuchi et al. 1977; Pomeranz and Chiu 1976; Mayer et al. 1977; Peets and Pomeranz 1978; Levine et al. 1978; Goldstein and Hilgard 1975).

Their results, though indirect, are supportive of the idea that the endorphin system may be involved in an endogenous pain modulation system. Such a system is likely to be of great survival value to the organism since it will permit it to experience pain as an important warning of tissue damage without the suffering of unbearable, disabling pain, except in pathological states. The importance of pain to the individual is best demonstrated by a disease called congenital insensitivity to pain. lndividuals with this condition are unable to feel pain from either visceral or superficial tissue damage. This is a serious pathology which results in a significantly shortened life expectancy. A number of laboratories including our own are currently studying such patients to determine whether an abnormality in the opiate receptorendorphin system may play a role in this inborn error. Preliminary reports have appeared that naloxone causes pain-associated reflexes and electrical discharges in such patients.

NARCOTIC ADDICTION

Another expected action of the endogenous opioid system is its participation in the development of narcotic addiction. The evidence for this turns out to be more difficult to obtain than that for pain modulation.

All opioid peptides will produce tolerance and physical dependence when injected repeatedly. This does not prove that tolerance/dependence develops to endogenously produced and released endorphins nor that these peptides and their receptors are involved in the formation of tolerance and dependence to narcotics.

A report by Simantov and Snyder (1976), for example, that enkephalin levels are elevated in brains of tolerant rats was recently refuted by experiments from the same laboratory (Childers et al. 1977). The earlier work which had been done using a radioreceptor assay was not supported when the much more specific radioimmunoassay was used.

Recently, however, there was a report (Su et al. 1978) that the intravenous administration of four milligrams of human /3-endorphin to human addicts led to dramatic improvement in severe abstinence syndromes. There was no euphoria and little adverse effect. ln a doubleblind study it was found that subjects were able to distinguish morphine and /3-endorphin. After endorphin treatment they felt thirsty, dizzy, sleepy, warm, and had "a strange feeling throughout the body." All these symptoms disappeared in 20 minutes, but the beneficial effects of endorphin on the withdrawal syndrome lasted for several days. The long-lasting suppression of especially the most severe symptoms of abstinence (vomiting, diarrhea, tremor, and restlessness) by a single dose of /3-endorphin suggested to the authors the possibility that this

endogenous peptide may indeed have a role in the mechanism of tolerance/dependence development to opiates.

Thus, a role of the opiate receptor-endorpt-.in system, while expected and fervently hoped for, has not yet been established. The evidence cited is sufficiently suggestive to warrant further research in this area.

For completeness, l should like to mention two recent developments of considerable interest for which the relationship to the opiate receptor is still unknown.

Walter et al. (1978) reported that it was possible to suppress the abstinence syndrome when rats were withdrawn from chronic morphine by administration of the dipeptide Z-Pro-D-Leu. There was no effect on the analgesic response to morphine. The mechanism of this phenomenon is not understood.

Based on the abundant literature which seems to implicate catecholamines in the actions of opiates. Gold et al. (1978) treated human heroin addicts with clonidine. ln a double-blind, placebo-controlled study, clonidine eliminated objective signs and subjective symptoms of opiate withdrawal for four to six hours in all addicts. ln an open pilot study, the same patients did well while taking clonidine for one week. All of the patients had been addicted to opiates for six to ten years and had been on methadone for six to 60 months at the time of the study.

CONCLUSION

The discovery of opiate receptors and their supposed endogenous ligands, the endorphins, has kindled the excitement and imagination of many scientists and, through ample coverage in the news media, of the general public as well. Hopes have been raised that these findings may contribute to the solution of a number of human pathologies ranging from intractable pain to mental disease.

There is not yet clear-cut evidence for the involvement of the opiate receptor in any human disease, but the evidence is sufficiently suggestive to encourage much further research in many competent laboratories and hospitals.

There is an interesting difference between this area of research and those involving receptors for other hormones and neurotransmitters. ln the other cases the endogenous ligand was discovered and known for some time before a receptor was postulated, searched for, and identified. The opiate field began with the identification of a drug receptor. The proof that such a receptor existed led to the search for endogenous ligands for the receptors and to the identification of a number of peptides with opioid activity. This approach is now being applied to other drug receptors, where it is felt unlikely that their existence anticipated the relatively recent development of the drug. A case in point is the discovery of specific binding sites for the tranquilizer benzodiazepine. Many laboratories are presently engaged in a search for the endogenous ligand for this receptor. Does the body produce its own tranquilizing substance? ls it one of the substances we are already familiar with or is it a substance yet to be identified?

This approach might conceivably be generalizable to other receptors for exogenous substances, such as drugs, viruses, and toxins. ln those cases in which a selective advantage to the organism is not evident, a search for an endogenous ligand and a physiological role for the receptor might prove worthwhile.

lt should be remembered that the opiate receptor field is only seven years old and fundamental information regarding the physiological role of the endorphins and of the receptor is still missing. A real understanding of the role of this receptor-ligand system in human disease may have to await the elucidation of its functions in normal animals and humans.

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