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physical dependence. The accumulation of carbon dioxide was shown to be one of the mechanisms involved in the acute diminution of morphine's depressant effects on respiration in the acute decerebrate cat (Martin and Eisenman 1962), and panting induced by morphine in the dog was due to an alteration of the temperature set point. Further, dissipation of body heat was responsible for acute tolerance to morphineinduced panting (Martin 1968). We further demonstrated in patients who were physically dependent on morphine that the partial pressure of carbon dioxide minute-volume stimulus response curve was shifted to the left indicating that the respiratory set point had been sensitized to CO, as a consequence of chronic morphine administration. This, to my knowledge, was the first experimental evidence that a homeostatic set point could be altered as the consequence of chronic administration of narcotics (Martin et al. 1968).
MULTIPLE OPIOID RECEPTORS
In 1967, I initiated studies reevaluating the abuse potentiality of the mixed agonists/antagonists, cyclazocine and nalorphine (Martin et al. 1965; Martin and Gorodetzky 1965), which were to have far-reaching impacts. We also initiated studies with a new antagonist with questionable analgesic activity, naloxone (Jasinski et al. 1967). As a consequence of the study of naloxone, which proved to be an antagonist without agonistic activity, and with the results that we obtained with cyclazocine and nalorphine, we made several speculations (Martin 1967):
1. We felt that for the first time, unequivocal evidence had been
obtained that morphine-like drugs were acting as agonists.
The action of mixed agonist/antagonists such as cyclazocine and nalorphine could not be explained on the basis of their interacting with a single (morphine) receptor and we postulated that there was another receptor (nalorphine).
We felt that some of the agonists/antagonists were acting as partial agonists.
4. The possibility of a naturally occurring agonist was entertained. We reasoned,
In attempting to explain the contrastimulatory properties of
(Martin 1967, p. 508)
For a time, I became involved in other pharmacologic problems, principally the issue of whether tryptamine was a neurotransmitter, and did not return to the issue of multiple opioid receptors again until Paul
Gilbert joined my laboratory as a graduate student. In the interim, however, Dr. Jasinski and I reinvestigated the abuse potentiality of pentazocine (Jasinski et al., 1970). In these studies we found that although pentazocine appeared to produce morphine-like subjective: effects in small to moderate doses, it would not suppress the morphine abstinence syndrome. This observation disturbed me and raised serious questions concerning the two-receptor theory of opioid action. When Gilbert initiated his thesis work (Gilbert and Martin 1976), we decided to reinvestigate the pharmacology of N-allyInormetazocine (SKF 10047), a benzmorphan derivative that had been studied by Keats and Telford (1964) and found to have a high degree of psychotomimetic and dysphoric activity. We had also known that high doses of naloxone were required to antagonize the effects of cyclazocine, in both the dog (McClane and Martin 1967) and in humans (Jasinski et al. 1968). We also studied ketocyclazocine and ethylketocyclazocine, which on the basis of work on the guinea pig ileum appeared to be strong agonists devoid of antagonist activity for which naloxone was a relatively impotent antagonist (Kosterlitz et al. 1973). From the results of these studies, it became quite apparent that we were mistaken in thinking that there were only two opioid receptors, and it was thus necessary to postulate a third receptor. We renamed the receptors H (for morphine), K (for ketocyclazocine), and o (for SKF 10047) and felt that these three receptors were respectively responsible for the euphorigenic, sedative, and dysphoric actions of the mixed agonists/antagonists. We also had obtained convincing evidence that buprenorphine was a partial agonist of morphine in the dog (Martin et al. 1976). Thus, it became apparent that the term agonist/antagonist had two meanings: (1) a partial agonist and (2) agonistic action at one receptor and antagonist or partial agonistic action at another receptor. These were the first receptors that were identified and differentiated on the basis of clinical and neuropharmacologic studies.
NARCOTIC ANTAGONIST IN THE TREATMENT
In our studies of cyclazocine and nalorphine (Martin et al. 1965; Martin and Gorodetzky 1965) we observed that tolerance developed to the subjective effects produced by cyclazocine and nalorphine and that following withdrawal of cyclazocine-dependent subjects, the abstinence syndrome had a long latency of onset. Based on these observations and theoretical considerations, we speculated that tolerance developed to cyclazocine's agonistic actions but not its antagonistic effect. We subsequently confirmed these speculations. I was privileged in being at the Addiction Research Center at a time when Dr. Abraham Wikler was evolving his ideas of conditioned abstinence and conditioned drugseeking behavior. We considered the possibility that if patients were made tolerant to the agonistic effects of cyclazocine, its prevailing antagonistic effects might allow the extinction of these two types of conditioning. The effects of heroin would be abolished, and thus could not be reinforcing by virtue of its producing feelings of wellbeing or inducing physical dependence. In any event, we did stabilize patients on high doses of cyclazocine and found that it not only blocked the effects of large doses of morphine and heroin but also prevented subjects from becoming physically dependent when morphine was administered chronically in high doses (Martin et al. 1966). Cyclazocine was given a clinical trial by Dr. Alfred Freedman of New York Medical
College and Dr. Jerome Jaffe, then of Albert Einstein College of Medicine. Both initiated studies of the utility of antagonist therapy in heroin addicts. Cyclazocine was disappointing in that it was not well accepted by addicts. In this regard, it should be mentioned that the administration, clinical investigators, and scientists of Sterling Winthrop were supportive of these investigations. It was felt that perhaps the dysphoric effects of cyclazocine might have been responsible for the lack of acceptance of it by addicts. On the basis of our studies with naloxone and cyclazocine, we speculated that naltrexone, which is chemically related to both naloxone and cyclazocine, might be a pure antagonist with a long duration of action. Indeed, the basic studies of Blumberg et al. (1967) indicated that it was a pure antagonist. Through the cooperation of Drs. Harold Blumberg, Ralph Jacobson, and Irwin Pachter, all then of Endo Pharmaceutical, we were able to initiate studies with naltrexone in humans and found indeed that it was a pure antagonist and that it had a sufficiently long duration of action to produce a high degree of antagonism of morphine when administered once a day orally.
Indeed, naltrexone has turned out to be a pure antagonist which has a long duration of action. It should be introduced into clinical medicine as the drug of choice for the treatment of narcotic overdose. In addition, it is a most satisfactory drug for antagonist therapy of heroin dependence.
in the early 1960s, at a time when Dr. Wikler was well into his studies of conditioned abstinence in the rat and at a time when Dr. Eisenman, Mrs. Sloan, and I were trying to dissect out the role of catecholamines in the morphine abstinence syndrome, it became apparent to us that many of the dimensions of tolerance and physical dependence on morphine in the rat were not well established, such as the rate of onset and particularly the duration of the abstinence syndrome (Martin et al. 1963). We thus initiated a study of morphine dependence in the rat and, to our surprise, found that the abstinence syndrome had two phases, an early and a late one, that were quite different. Although | maintained an interest in this problem, I did not return to it for several years. In 1967, we initiated a long-term reinvestigation of morphine dependence in humans (Martin and Jasinski 1969) and found that indeed humans also exhibited both an early and a protracted abstinence syndrome. However, the signs of protracted abstinence syndrome were small in magnitude and, although demonstrable in an experimental setting using a paired comparison, could not be identified or diagnosed on the basis of physiologic abnormalities in a clinical setting. With the introduction of methadone maintenance, it was decided to reinvestigate both the short- and the long-term effects of methadone maintenance under carefully controlled experimental conditions. Previous studies of protracted abstinence were extended by making three additional measures: (1) the psychometric changes that occur during a cycle of addiction, (2) the effects of a cycle of addiction on EEG and sleep, and (3) the effects of addiction on hormonal function. By far the most exciting results that were obtained were with regard to the psychologic changes. It was found that during chronic methadone administration negative feeling states prevailed and that these were exacerbated and persisted through both early abstinence and protracted abstinence (Martin et al. 1973). We then initiated study of protracted
abstinence in the dog and extended our observations by determining the responsivity to nociceptive stimuli during a cycle of morphine dependence (Martin et al. 1974). In these studies, it was found that the dog also exhibited a protracted abstinence syndrome and that during protracted abstinence responsivity to strong nociceptive stimuli was enhanced.
THE PSYCHOPATHOLOGY OF THE
The results we obtained in humans and in the dog during protracted abstinence suggested that protracted abstinence was associated with an exacerbation of feelings of hypophoria and that these feelings of hypophoria might be associated with an increased need state.
These concepts of an affective state that was present in addicts became clarified. In my clinical experience with addicts who had participated in studies on the ward of the Addiction Research Center, I recognized a number of diatheses, the most prominent of which were feelings of poor self-image and unpopularity. Several investigators had observed that drug abusers had had elevations on the depression and the psychopathic deviate scales of the MMPI, yet on the basis of experiences on the ward of the Addiction Research Center few patients showed any signs or symptoms commonly associated with depression. Table 1 contrasts the feelings of euphoria, hypophoria, and depression. As can be seen, hypophoria is in many areas the polar opposite of euphoria, being associated with feelings of unpopularity, being unappreciated, ineptness, and inefficiency, whereas patients under the influence of euphoria-producing drugs such as morphine-like narcotic analgesics, amphetamine-like agents, LSD-like hallucinogens, and barbiturates feel popular, liked, appreciated, competent, and efficient. However, patients who have feelings of hypophoria can readily be differentiated from depressed patients in that they feel hopeful, worthy, can experience joy, can laugh, and feel guiltless. It became apparent that more information was needed to establish the concept of hypophoria as a unique and pathologic affective state and to begin speculations about
TABLE 1.-Characteristics of euphoric, hypophoric,
and depressive feelings
the nature of this hypophoria. Our studies on protracted abstinence had already indicated that long-term exposure to opiates gave rise to persisting and enhanced hypophoric feelings. We felt there was some evidence that suggested that these feelings might be related in some way to exaggerated need states which in turn were related to increased egocentricity. Hypophoria, exaggerated need states, and egocentricity increase the probability that individuals will have antisocial feelings and exhibit impulsivity. With this theoretical basis, a maturation scale was constructed that had items that were related to egocentricity, characterized by selfishness, inability to love, and callousness; impulsive behavior, characterized by thoughtlessness and uninhibited behavior; a need scale, related to sexual desires, hunger, body health, pain, and general wanting; a hypophoria scale, related to a negative perception of life, of poor self-image, feelings of being disrespected, disapproved of, and unappreciated, as well as feelings of ineffeciency and ineptness, withdrawal from competition, worry, and anger; and finally an antisocial scale consisting of items relating to antisocial feelings, feelings of nonconformity, poor judgment, and lack of social concern (Martin et al. 1977).
To study further the possibility that addicts and alcoholics might have exaggerated need states, we compared a group of alcoholics and addict prisoners with a group of nonsociopathic control subjects. The maturation scale and MMPI was administered to these subjects and a detailed history of antisocial behavior was obtained. In addition, plasma levels of follicle-stimulating and luteinizing hormones and testosterone were measured. It was found that the alcoholics, prisoners, and addicts had significantly elevated levels of luteinizing hormones and testosterone as well as significant elevations on the impulsivity, egocentricity, need, hypophoria, sociopathy, and maturation scales. These findings were supportive of the concept of exaggerated need states and of an affective disorder being of importance in drug abusers and alcoholics and that persons with a character disorder which manifested itself in an antisocial personality could have a biologic pathology.
NEUROTRANSMITTERS AND SUBJECTIVE STATE
Part of the Addiction Research Center's effort was to develop predictors of the abuse potential of psychoactive drugs. Drs. Harris Hill and Charles Haertzen developed a 550-item questionnaire that was especially useful in identifying and characterizing the subjective effects of drugs. Much of this work has been summarized by Haertzen (1966). Among the scales that were developed by Haertzen, the MBG scale (morphine benzedrine group scale) proved to be the most useful measure of the euphorigenic actions of drugs. Many items on this scale related to feelings of well-being, popularity, and efficiency, and in this regard were the polar opposites of the hypophoric subjective state. Amphetamine (Martin et al. 1971), narcotic analgesics (Jasinski et al. 1971), and pentobarbital (McClane and Martin 1976) caused dose-related elevations of MBG scale scores. This information was interpreted as indicating that morphine, amphetamine, and pentobarbital may be drugs that were used by patients as an antidote for their hypophoric feelings and to produce feelings of well-being.
Other drugs that will produce feelings of well-being include the LSDlike hallucinogens. A large number of investigators have demonstrated that many of the actions of the amphetamine-like drugs are attributable