Interactions between the discriminative stimulus effects of mu and kappa opioid agonists in the squirrel monkey

A series of mu and kappa opioid agonists with varying degrees of selectivity were evaluated for their agonist and antagonist effects in squirrel monkeys trained to discriminate either the selective mu agonist fentanyl or the selective kappa agonist U50,488 from water. In the fentanyl-trained monkeys, fentanyl, as well as the less selective mu agonists buprenorphine and (-)-metazocine, produced dose-dependent and complete substitution for the training stimulus. U50,488 produced neither agonist nor antagonist effects in the fentanyl-trained monkeys, but the less selective kappa agonists bremazocine and tifluadom generally produced either agonist or antagonist effects, depending on the monkey tested. In the U50,488-trained monkeys, U50,488, bremazocine and tifluadom all produced a dose-dependent and complete substitution for the training stimulus. Fentanyl produced neither agonist nor antagonist effects in the U50,488-trained monkeys, but buprenorphine and (-)-metazocine antagonized the discriminative stimulus effects of U50,488. The inability of the selective mu agonist fentanyl and the selective kappa agonist U50,488 to antagonize each other's discriminative stimulus effects suggests that the stimulus effects mediated by mu and kappa opioid receptors in squirrel monkeys do not interact with a common biologic substrate. Rather, these results suggest that the stimulus effects mediated by mu and kappa receptors function independently of one another. Interactions involving the less selective mu agonists buprenorphine and (-)-metazocine, or the less selective kappa agonists bremazocine and tifluadom, can be explained on the basis of the low receptor selectivity of these drugs.