Behavioral Pharmacology of Narcotic Antagonists

2015

Narcotic antagonists are currently the major pharmacological alternative to methadone for the long-term treatment of narcotic addiction. The clinical utility of antagonist treatment is undergoing continuing evaluation (). Within the last five years, there have been several comprehensive reviews of research on narcotic antagonist drugs (). This review will focus upon some recent behavioral studies of narcotic antagonist drugs in man and in animals.

It is now apparent that antagonist drugs may have a number of complex behavioral effects, in addition to antagonism of the pharmacological effects of opiate drugs (). Recent explorations of the aversive properties of some antagonists () have been complemented by studies of the positive reinforcing qualities of antagonist drugs. The finding that opiate dependent monkeys will work to produce an infusion of a narcotic antagonist under certain conditions () suggests the complexity of the process of drug-related reinforcement (). Narcotic agonists and antagonists each may maintain behavior that leads to their administration.

Of the several compounds which have narcotic antagonist properties), only two appear to be relatively “pure” antagonists with minimal agonistic activity. Consequently, naloxone and more recently naltrexone have become the antagonists of choice for most behavioral studies. The antagonists cyclazocine and nalorphine have been found to be partial agonists. For example, nalorphine may produce dysphoria and psychotomimetic effects in man, as well as autonomic effects similar to those produced by morphine (). Although some antagonists have analgesic potency, adverse side effects have limited their clinical use for analgesia (). However, it is important to recognize that even the “purest” antagonists may have some agonistic properties at sufficiently high doses ().

Naloxone and naltrexone differ in potency and duration of action. Naloxone is estimated to have a duration of action of approximately four hours, which makes it especially useful for behavioral studies. Naltrexone is estimated to be between two and eight times more potent than naloxone, depending upon the test system employed (). In man, the antagonist actions of naltrexone appear to persist beyond 24 hours (), even though analysis of urinary excretion patterns indicate that naltrexone is cleared within 16 to 24 hours (). Recent evidence suggests that beta-naltrexol, the major urinary metabolite of naltrexone, may contribute to its long duration of action in man (). However, chronic high doses of naltrexone (100 mg/day) do not result in the accumulation of either naltrexone or beta-naltrexol (). Although beta-naltrexol is the predominant urinary metabolite in man, nearly equal proportions of naltrexone and beta-naltrexol are excreted in the urine of monkey (). The implication of these findings for the apparent difference in duration of naltrexone blockade in man and monkey remains to be clarified ().

Antagonism of opiate effects

The primary effects of narcotic antagonists are to reverse or to block the pharmacological effects of opiates. Pre-treatment with a narcotic antagonist will prevent the physiological and behavioral effects of acute opiate administration. Chronic administration of narcotic antagonists also blocks the development of tolerance and physical dependence upon opiates (). Administration of narcotic antagonists to an opiate dependent person or animal will precipitate an opiate withdrawal syndrome (). The severity of antagonist precipitated opiate withdrawal appears to be antagonist-dose related (). The capacity of these compounds to reverse respiratory depression induced by opiates has long been an effective tool for emergency ward treatment of overdose.

There has been considerable progress towards understanding the mechanism of action of narcotic antagonists within the past five years. Several laboratories have found stereospecific opiate receptor sites in brain which appear to be binding sites for endogenous neural ligands termed endorphins (). It has been hypothesized that endorphins may act to inhibit or modulate neural responses to painful stimuli (cf. 31). Opiate antagonists may compete with exogenous morphine-like drugs for stereospecific opiate receptor sites. However, Jaffe and Martin () suggest that the notion of competitive antagonism at a single receptor site cannot account for many of the interactions between opioids and opioid antagonists. For example, although most antagonists do not induce tolerance or physical dependence, antagonists of the nalorphine type may produce a withdrawal syndrome which is qualitatively different from the morphine withdrawal syndrome. Moreover, partial agonists of the nalorphine type may substitute for morphine at relatively low levels of physical dependence and precipitate withdrawal at high levels of morphine dependence. These and other observations have led to the hypothesis that specific receptors or receptor configurations may exist for antagonists and for opiates ().

Some effects of antagonists on food and shock maintained behavior

Over the past decade, behavioral pharmacologists have studied a variety of narcotic antagonists. There is little question that narcotic antagonists will effectively block or reverse the behavioral effects of opiates in nondependent animals, in a dose-related manner. Behavioral effects have been variously defined as rate of response for food and efficiency of avoidance responding under a variety of single and multiple schedules of reinforcement (). The effects of narcotics and antagonists on multiple fixed interval-fixed ratio schedules of food presentation have been reviewed recently ().

It is generally found that high doses of morphine decrease the rate of operant responding for another reinforcer such as food. However, very small doses of morphine may increase a pigeon’s rate of response for food. Increases of about 50 percent have been observed in the fixed interval component of a multiple fixed ratio-fixed interval schedule. Certain antagonists have also been shown to increase rates of responding in the fixed interval component of the multiple schedule at low doses and decrease rates at high doses (). Narcotic antagonists can block the rate decreasing effects of opiates at dose levels which do not produce direct behavioral effects, For example, pretreatment with naloxone (0.1 mg/kg) blocked both the rate increasing and the rate decreasing effects of morphine on schedule-controlled performance for food reinforcement. However, naloxone doses as high as 30 mg/kg did not antagonize the rate decreasing effects of cyclazocine ().

Naltrexone and diprenorphine (0.1 mg/kg) appear to have comparable potency for blockade of the effects of an acute dose of morphine (30 mg/kg) on food-maintained responding in pigeon (). Those antagonists appear to be as much as three times more potent than naloxone (). Naltrexone can block the effects of morphine administered as long as six hours after acute antagonist administration in pigeon ().

Species-related differences in response to narcotic antagonists have been reported (). For example, nalorphine decreased rates of food-maintained responding in squirrel monkeys and increased response rates in pigeons under comparable schedule conditions and across a comparable dose range, whereas high doses of naloxone decreased response rates in both monkeys and pigeons and produced gross tremors and vomiting (). Naloxone did not antagonize the rate decreasing effects of nalorphine at doses which completely antagonized the effects of morphine. The interactions between antagonists and consequent effects on behavior do not appear to be reliably predicted from the behavioral effect of an antagonist plus a narcotic drug.

Effects of antagonists of opiate self-administration

Aversive effects of antagonists

Clinical studies indicate that administration of narcotic antagonists such as nalorphine and cyclazocine may produce dysphoria, anxiety, and a spectrum of feelings of unreality, including hallucinosis in some individuals (). Comparable effects have not been reported following acute administration of naloxone. Dysphoric and psychotomimetic side effects do not appear to be a prominent feature of naltrexone administration.

Some morphine antagonists have negative reinforcing properties in opiate naive monkeys (). Monkeys worked to avoid or escape nalorphine (10-500 mcg/kg/inj) and cyclazocine (2.5-10 mcg/kg/ inj); however, naloxone (5-100 mcg/kg/inj), pentazocine and propiram (50 mcg/kg/inj) did not maintain escape or avoidance behavior at rates higher than saline (). These data suggest that the aversive properties of certain antagonists are not solely a function of opiate dependence.

Primates will work to avoid or to terminate infusions of narcotic antagonists under a variety of conditions (). Nalorphine. naloxone, pentazocine, and propiram have been shown to maintain escape and avoidance behavior in morphine-dependent monkeys. Primates will also work to terminate a discriminative stimulus which was previously associated with the administration of a narcotic antagonist (). However, a number of compounds other than narcotic antagonists have also been shown to maintain behavior leading to termination or postponement of injections ().

Antagonist self-administration

 

Selections from the book: “The International Challenge of Drug Abuse”. Robert C. Petersen, Ph.D., editor. A monograph based on papers presented at the World Psychiatric Association 1977 meeting in Honolulu. Emphasis is on emerging patterns of drug use, international aspects of research, and therapeutic issues of particular interest worldwide. National Institute on Drug Abuse Research Monograph 19, 1978.