Assessment of the kappa antagonist properties of buprenorphine

In an attempt to assess the kappa antagonist properties of buprenorphine within a conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Following the acquisition of the discrimination, buprenorphine stimulus control generalized completely to the mu agonist morphine in four of the five subjects tested while morphine stimulus control completely generalized to buprenorphine in two of five subjects and partially generalized in the remaining three. Furthermore, buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. That morphine and buprenorphine displayed some degree of cross generalization suggests that these compounds share some stimulus property, presumably their agonist activity at the mu receptor, and that the mu activity of these compounds was used in the establishment of the discrimination, a conclusion supported by the fact that compounds with mu antagonist activity (e.g., naloxone, MR2266) blocked both buprenorphine and morphine stimulus control. The failure of buprenorphine to generalize to compounds with kappa antagonist properties suggests that animals trained to discriminate buprenorphine from its vehicle do not use the kappa antagonist activity of the drug in the establishment of the discrimination. Because it has been reported that the mu properties of buprenorphine can overshadow its kappa antagonist properties in opiate-naive subjects (Negus et al., 1989), similar substitution profiles were examined in morphine-tolerant animals (Experiment 2), a manipulation known to attenuate this overshadowing. Specifically, opiate-tolerant rats were trained to discriminate buprenorphine from distilled water and then tested for the generalization of this control to the mu agonist morphine and the kappa antagonist MR2266. Exposure to morphine shifted the morphine generalization function to the right (indicating tolerance), yet MR2266 continued to fail to substitute for buprenorphine, again providing no evidence for the ability of buprenorphine's kappa activity to support drug discrimination learning, even in opiate-tolerant subjects. This failure of the kappa antagonist properties of buprenorphine to support drug discrimination learning (DDL) may reflect a general difficulty in establishing control with kappa antagonists. This hypothesis was tested in Experiment 3 in which discriminative training was attempted with various doses of the kappa antagonist, MR2266. There was no evidence of the acquisition of discriminative control with MR2266 even with repeated training and at high doses, suggesting that kappa antagonists do not support drug discrimination learning. Although the present series of experiments demonstrate that different receptor activity of compounds which act on multiple receptors may not be equally salient in their behavioral or discriminative effects, the basis for these differences remains unknown.