Discriminative stimulus effects of the opioid antagonist diprenorphine in the squirrel monkey

SE DeRossett and SG Holtzman

Squirrel monkeys were trained in a discrete-trial avoidance paradigm to discriminate i.m. injections of the opioid antagonist diprenorphine (0.1 mg/kg) from vehicle. When the monkeys could complete reliably at least 22 trials of a 25-trial session on the choice level appropriate for the substance injected before the session (i.e., diprenorphine or vehicle), tests of stimulus generalization to novel drug conditions were conducted. Mu receptor agonists (morphine, etorphine and buprenorphine) and kappa receptor agonists (ethylketocyclazocine, nalorphine and I-N-allylnormetazocine) produced dose-dependent diprenorphine-like discriminative effects. The dextrorotatory isomer of N-allynormetazocine was almost two-orders of magnitude less potent than the levorotatory isomer in this respect and phenycyclidine generalized to diprenorphine only partially, suggesting that the phencyclidine/sigma site does not have a prominent role in the discriminative effects of diprenorphine. Other nonopioid drugs (d- amphetamine, mescaline and pentobarbital) also did not produce discriminative effects comparable to those of the training drug. The pure opioid antagonists, naloxone, naltrexone, and WIN 44,441-3 [(2- alpha-6 alpha, 11S)-(-)-1-cyclopentyl-5-(1,2,3,4,5,6-hexahydro-8- hydroxy-3,6,11-trim eth yl-2, 6-metheno-3-benzazocin-11-yl)-3- pentanone] occasioned responding primarily on the lever appropriate for vehicle. Naloxone (1.0 mg/kg) blocked surmountably the diprenorphine- like discriminative effects of the mu and kappa agonists, displacing generalization curves to the the right by 10- to 100-fold; however, naloxone failed to shift the curve for diprenorphine itself. Thus, in the squirrel monkey diprenorphine has discriminative stimulus effects in common with mu- and kappa-opioid agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 237, Issue 2, pp. 437-444, 05/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics