Agonist and antagonist effects of prototype opiate drugs in rats discriminating fentanyl from saline: characteristics of partial generalization

Abstract

The experiments reported here characterized the partial generalizations that prototype opiate drugs may produce in rats that are trained to discriminate 0.04 mg/kg of fentanyl from saline. Cyclazocine, nalorphine, ketocyclazocine and N-allylnormetazocine produced partial generalization with fentanyl; the same compounds also partially antagonized fentanyl. The fentanyl-like and the fentanyl-antagonist effects of these compounds occurred within similar ranges of dose. An orderly incompatibility was apparent between the agonist and antagonist effects produced by each drug; cyclazocine, for example, was unlikely to antagonize fentanyl in animals in which it produced generalization, whereas it did antagonize fentanyl in animals in which it produced no generalization. Cyclazocine, nalorphine, N-allylnormetazocine and naloxone produced either fentanyl-like or fentanyl-antagonist effects in all animals tested. A reliable relationship was apparent among the agonist and antagonist effects of different opiate drugs; rats that generalized cyclazocine also were likely to generalize nalorphine and ketocyclazocine and were relatively less responsive to cyclazocine, nalorphine, N-allylnormetazocine and naloxone as antagonists of fentanyl. The results point to the importance of a number of new methods in the analysis of drug discrimination data. Among these are the analysis of individual generalization data and the examination of agonist and antagonist effects of test drugs in the same animals. A parsimonious molecular interpretation of the data can be offered by assuming that morphine, ketocyclazocine, cyclazocine, nalorphine, N-allylnormetazocine and naloxone have affinity for, but differ in activity at, an opiate receptor where fentanyl acts to produce discriminative effects.