The effects of chronic morphine on the generalization of buprenorphine stimulus control: an assessment of kappa antagonist activity.

Rats trained to discriminate the mixed mu agonist/kappa antagonist buprenorphine from its vehicle generalize buprenorphine control to morphine. Buprenorphine, however, does not generalize to MR2266. The generalization to morphine suggests that buprenorphine's mu agonist properties mediated in part its discriminative control. The failure to generalize to MR2266, a compound reported to block kappa-mediated effects, however, suggests that its kappa antagonist activity was not involved in its discriminative effects. The ability of buprenorphine's mu (but not kappa) activity to establish stimulus control may be a function of the overshadowing of the kappa properties of buprenorphine by its concurrent mu activity. To test this possibility, in the present experiment rats were chronically exposed to morphine prior to buprenorphine discrimination training. This procedure has been reported to result in tolerance to buprenorphine's mu agonist effects and a more pronounced display of its kappa antagonist properties. The rats were then tested for the generalization of buprenorphine control to morphine, MR2266, and pentobarbital. As expected, buprenorphine failed to generalize to the nonopioid pentobarbital. Although subjects were tolerant to morphine (as evidenced by reductions in morphine-induced behavioral effects and a rightward shift in the doses of morphine substituting for buprenorphine), buprenorphine still failed to generalize to MR2266. The failure of buprenorphine to generalize to MR2266 under conditions that should have allowed for the development of stimulus control by buprenorphine's kappa antagonist activity was discussed in terms of the general inability of kappa antagonist activity to support discrimination learning.