RT Journal Article
SR Electronic
T1 OPIOID ANTAGONISTS
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 463
OP 521
VO 19
IS 4
A1 MARTIN, W. R.
YR 1967
UL http://pharmrev.aspetjournals.org/content/19/4/463.abstract
AB Several investigators have postulated that nalorphine acts competitively in antagonizing the effects of opioids (293), but the corollary of this hypothesis that opioids are agonists was first explicitly stated by Van Rossum (333). In arguing the point whether morphine was the agonist or antagonist and nalorphine the antagonist or agonist, Van Rossum felt that morphine was more likely the agonist and nalorphine the antagonist because nalorphine had a larger group substituted on the nitrogen. Archer and Harris (6) buttressed this argument by summarizing studies in which narcotic antagonists appeared to act competitively against narcotic analgesics. The argument is further strengthened by the finding that naloxone acts as an antagonist in dose levels that are devoid of agonistic or contrastimulatory effects. The nature of the agonistic action of morphine in the central nervous system has not been demonstrated. There is no question that its action on the intestine in inhibiting acetylcholine release is a competitively antagonizable agonistic effect, but acetyicholine antagonists and anticholinesterases do not respectively mimic or antagonize the central actions of morphine. Although these facts do not conclusively reject inhibition of acetylcholine release as a mechanism of morphine's central action, they do not support this hypothesis, even though morphine prevents the release of acetylcholine in the brain (15). Either directly or indirectly, morphine causes changes in the release of norepinephrine, epinephrine, dopamine, histamine, and serotonin. With such broad actions on neurohumors, the possibility that it alters the release of yet other unidentified neurohumors cannot be excluded. Whatever the mode of action of opioids, clearly agents that occupy the receptor sites of the opioids differ in their ability to induce pharmacological actions. Near the two extremes of activity are morphine, representative of an active agonist, and naloxone, representative of an agonist with no activity and a competitive antagonist. Differences in degrees of activity among opioid antagonists have been seen in a number of functional systems, including those responsible for analgesia, respiratory depression, miosis, and inhibition of the release of acetylcholine. The possibility that opioids could have different levels of intrinsic activity has been proposed (228). Obviously, the basis for differences in activity between the agents that seem to occupy the opioid receptor cannot even be rigorously studied until the modes of action of the opioids have been elucidated, and possibly the basic mechanisms governing the release of neurohumors and the excitability of neurons discovered; however, for heuristic reasons it may be worthwhile enumerating some of the possible mechanisms that have been proposed for other agonists and systems. Ariëns et al. (8) have suggested that the magnitude of intrinsic activity is associated with effectiveness of the drug-receptor interaction, i.e., with the intimacy of binding at all necessary sites. Alternatively, they have suggested that the agonist could serve as a cofactor, some agonists being effective cofactors (e.g., furnishing hydrogen ions), while others would be less effective. The effectiveness would be independent of the tightness of the union of the cofactor with the enzyme. The known facts about opioid analgesics and antagonists do not really allow critical testing of these hypotheses. Paton (271) has proposed that the rate of occupation of receptors by the agonist may determine the magnitude of effect. This theory predicts that activity is directly related to the dissociation constant at an equilibrium state and that agents that are more tightly bound would be weaker agonists, and conversely, more effective antagonists. This hypothesis cannot be rejected for the narcotic analgesics, but the following observations argue against it: (1) The duration of action of antagonists and partial agonists as antagonist would be expected to be longer than their actions as agonists and longer than the actions of pure agonists. Naloxone, an antagonist which is nearly devoid of agonistic activity, has a shorter duration of action than cyclazocine, an active agonist and antagonist. An even more critical piece of evidence is that both the agonistic and antagonistic effects of the narcotic antagonist cyclazocine persist for many hours. (2) Nalorphine egresses from the brain more rapidly than morphine. This observation is not critical, because, as has been pointed out, the agonistic actions of nalorphine persist longer than its presence in the brain. This suggests that chemical determinations are not primarily measuring drug bound to active receptors. Mackay (220) has suggested that the agonistic actions of drugs may be related to the density of their influx through the effector membrane. This hypothesis does not fit with the observation that pharmacological actions, as well as brain levels of both opioid and opioid antagonists, continue at high levels at times when the plasma concentrations have decreased to negligible levels. At the present time, the most attractive drug-receptor hypothesis is that opioids' action is a consequence of two factors: the proportion of the receptors occupied by the analgesic, and the intrinsic activity of the analgesic. Testing of this hypothesis in a number of functional systems is complicated by the fact that they are concerned with homeostatic regulation and that acute tolerance and dependence develop in them. Antagonists need only partially antagonize the effects of the opioid on a homeostatic mechanism to create an error force that will drive compensatory mechanisms above their control level of function. A similar situation may exist for systems that are either acutely or chronically dependent. Among the observations that argue against accepting the concept that opioid antagonists are competitive antagonists are the facts that: (1) Under some circumstances, the actions of nalorphine add to those of morphine, while under other circumstances they antagonize the actions of morphine; and (2) nalorphine exhibits contrastimulatory actions in its own right. With regard to the former observation, when the properties of partial agonists (agents with moderate or low intrinsic activity) are recognized, as well as the importance of homeostasis and dependence in the response to them, many of the paradoxical observations can be adequately explained. In attempting to explain the contrastimulatory properties of the opioid antagonists, one is forced to reconsider the nature of the agonistic actions of the narcotic analgesics. One can assume, for argument sake, that opioids mimic a naturally ongoing process. If this hypothesis is true, then it would not be unreasonable to assume that those antagonists with low intrinsic activity would antagonize not only morphine-induced activity, but the naturally ongoing activity that is similar in nature to the effects of morphine with the result that an antimorphine effect would become manifest. The effects of the opioid antagonists on several functional systems, such as EEG changes in the rabbit, respiratory changes in certain anesthetized preparations and the extensor thrust reflex in the spinal dog, seem consistent with this formulation, but the preponderance of observations indicates that for most systems either the opioid antagonists have no action or their actions resemble those of morphine. It can be assumed that for some sites affected by opioids there is no natural morphine mimetic ongoing process, whereas there are naturally ongoing morphine mimetic processes at other sites. A more serious problem bearing on the issue of competitive inhibition is the biphasic dose response curves obtained by Houde and Wallenstein (152), Rubin et al. (283) and Yim et al. (370) for the analgesic activity of mixtures of opioids and opioid antagonists. This type of dose response relationship cannot be obtained by assuming there is one analgesic receptor and that competitive antagonism or competitive dualism obtains. It can be explained by assuming that there are two analgesic receptors, one where morphine acts as an agonist and nalorphine as a competitive antagonist, and the other where morphine is inactive and nalorphine is an agonist. The fact that nalorphine and morphine produce different types of subjective effects is also consistent with the idea that they may act at different sites. This is buttressed by the observation that subjects tolerant to subjective effects of morphine are not cross tolerant to the psychotomimetic effects of cyclazocine. The fact that subjects dependent on the narcotic antagonists nalorphine and cyclazocine exhibit an abstinence syndrome that is qualitatively different from the morphine abstinence syndrome also supports this hypothesis. The fact that naloxone can antagonize the agonistic actions of both the narcotic antagonists and the narcotic analgesics would indicate that although these receptors are distinguishable they must have very similar stereochemical configurations. In this regard, Portoghese (278), on the basis of structural considerations, has also suggested that there may be several species of analgesic receptors. Taber et al. (315) have also suggested that the narcotic antagonists may have a different site of action from that of the opioids in producing analgesia, and base their argument on the difference in slopes of the dose response curves of opioid and analgesic opioid antagonists. The observation that the agonistic antagonists nalorphine and cyclazocine can induce tolerance to their agonistic effects, but not to their antagonistic effects and physical dependence, whereas the antagonist naloxone does not induce either tolerance or dependence, strongly suggests that both tolerance and dependence are induced by the agonistic effect, not by receptor occupation. When naloxone is administered chronically, its blocking action persists, indicating receptor occupation; however, neither tolerance nor dependence is induced. Studies with opioid antagonists clearly indicate that morphine and other narcotic analgesics act at all levels of the central nervous system and in the peripheral nervous system, and that whatever their mode of action, it is on a very fundamental, basic, and widespread neuronal process. 1967 by The Williams & Wilkins Co.