Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity.

Using the conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Specifically, animals were injected with buprenorphine or morphine prior to a saccharin-LiCl pairing and the drug vehicle prior to saccharin alone. By the fifth conditioning trial, animals differentially consumed saccharin on the basis of administration of the drug or its vehicle. In subsequent generalization tests, 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. Buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. Morphine also failed to generalize to MR2266, but did generalize to 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. That buprenorphine failed to generalize to compounds with kappa antagonist activity 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. The basis for the differential ability of various receptor subtypes to mediate the discriminative properties of compounds with mixed receptor activity was discussed.