Discriminative Stimulus Effects of the Mixed-Opioid Agonist / Antagonist Dezocine : Cross-Substitution by Mu and Delta Opioid Agonists 1

The purpose of this investigation was to evaluate the discriminative stimulus effects of the mixed-opioid agonist/antagonist dezocine. In pigeons trained to discriminate 1.7 mg/kg dezocine from saline, a series of opioids with activity at the mu opioid receptor substituted completely for the dezocine stimulus with a rank order of potency similar to that obtained in other assays sensitive to the effects of mu agonists (i.e., fentanyl .[-]-cyclazocine .buprenorphine 5 butorphanol .l-methadone .nalbuphine .[-]-metazocine .morphine). (-)-N-allylnormetazocine and (1)-propoxyphene substituted partially for the dezocine stimulus, an effect obtained even when tested up to doses that suppressed responding. Naloxone (0.1 10 mg/ kg) antagonized the stimulus effects of dezocine, (1)-propoxyphene and fentanyl in a dose-related manner, whereas doses of naloxone that antagonized fentanyl’s rate-decreasing effects failed to antagonize the rate-decreasing effects of dezocine and (1)-propoxyphene. A 10-mg/kg dose of the mu-selective, noncompetitive antagonist b-funaltrexamine was more effective against the stimulus effects of dezocine and nalbuphine than against morphine and fentanyl. As was observed with naloxone, b-funaltrexamine failed to antagonize dezocine’s ratedecreasing effects. The delta agonists BW373U86 and SNC80 substituted partially for the dezocine stimulus, and these effects were reversed by doses of the delta-selective antagonist naltrindole (0.1 and 1.0 mg/kg) that had no effect on the dezocine stimulus. Naltrindole also antagonized the rate-decreasing effects produced by BW373U86 and SNC80, but not those of dezocine. The kappa agonists bremazocine, spiradoline, U50,488 and U69,593 failed to substitute for the dezocine stimulus. The kappa-selective antagonist norbinaltorphimine (1.0 mg/kg) failed to antagonize dezocine’s stimulus or ratedecreasing effects. The present findings indicate that dezocine shares similar stimulus effects with both mu and delta agonists, its stimulus effects are reversed by mu-selective antagonists, and its rate-decreasing effects are not mediated by activity at mu, kappa or delta opioid receptors. Dezocine is a recently marketed opioid-analgesic that has a profile of pharmacological activity characteristic of a mixedopioid agonist/antagonist (Malis et al., 1975; Rowlingson et al., 1983; O’Brien and Benfield, 1989). As with many mixedopioid agonist/antagonists, dezocine can precipitate withdrawal in morphine-dependent animals and antagonize the loss of the righting reflex, respiratory depression and body rigidity induced by high doses of morphine (Malis et al., 1975). Moreover, the maximal effects produced by dezocine in some assays of respiratory depression and antinociception are less than those produced by morphine (Rowlingson et al., 1983; Romagnoli and Keats, 1984; O’Brien and Benfield, 1989). Under some conditions, dezocine’s behavioral profile is similar to that of morphine and other mu agonists. For example, dezocine is self-administered by macaque monkeys when substituted for codeine, substitutes for the stimulus effects of morphine in rats and squirrel monkeys (Schaefer and Holtzman, 1981; Young et al., 1992), and produces a constellation of morphine-like subjective effects (e.g., drug liking) in humans without histories of drug abuse and in nondependent opioid drug users (Jasinski and Preston, 1985; Zacny et al., 1992). Furthermore, in both rats and humans dezocine’s antinociceptive effects are reversed by doses of naltrexone or naloxone that also reverse the effects of mu agonists (Malis et al., 1975; Gal and DiFazio, 1984; Walker et al., 1996). A number of studies also suggest that dezocine may have activity at sites other than the mu opioid receptor. For example, in humans dezocine can produce effects that are not typical of mu agonists, such as dysphoria and sedation (Romagnoli and Keats, 1984; Jasinski and Preston, 1985; Zacny et al., 1992), and there are anecdotal reports suggestive of psychotomimesis (Romagnoli and Keats, 1984). In patas monkeys responding on a repeated acquisition procedure, where mu agonists do not markedly alter accuracy of reReceived for publication December 24, 1996. 1 This work was supported by United States Public Service Grant DA10277 from the National Institute on Drug Abuse. ABBREVIATIONS: FR, fixed ratio; bFNA, b-funaltrexamine; nor-BNI, norbinaltorphimine; ED, effective dose; CL, confidence limits. 0022-3565/97/2833-1009$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 283, No. 3 Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 283:1009–1017, 1997 1009 at A PE T Jornals on O cber 5, 2017 jpet.asjournals. org D ow nladed from sponding, dezocine decreases accuracy of responding in a dose-related manner (Moerschbaecher et al., 1987). Moreover, in rhesus monkeys responding on a shock titration procedure, doses of naloxone that antagonize the effects of morphine are only minimally effective against the effects of dezocine (Malis et al., 1975). The purpose of the present study was to evaluate the discriminative stimulus effects of dezocine. To this end, pigeons were trained to discriminate a 1.7-mg/kg dose of dezocine from saline, and substitution tests were conducted with mu agonists (fentanyl, l-methadone, morphine, buprenorphine, butorphanol, nalbuphine, [1]-propoxyphene), kappa agonists (bremazocine, spiradoline, U50,488, U69,593) and delta agonists (BW373U86, SNC80). To evaluate further the receptor-mediated activity of dezocine, substitution tests were conducted with the stereoisomers of various opioids (cyclazocine, n-allylnormetazocine, metazocine) and antagonism tests were conducted with naloxone as well as a muselective (bFNA), kappa-selective (nor-BNI) and delta-selective (naltrindole) antagonist. Finally, to evaluate the pharmacological selectivity of the dezocine stimulus, substitution tests were conducted with selected nonopioid compounds (cocaine, oxotremorine, [1]-amphetamine, pentobarbital, chlordiazepoxide, clonidine).