The proposed research will systematically examine associative and nonassociative influences on the development of tolerance to the analgesic effects of opioids. Associative tolerance will be produced by pairing a distinctive context with a high dose of drug at a long interdose interval. Nonassociative tolerance will be produced by exposure to a high dose of drug at a short interdose interval. The studies will evaluate interactions between associative and nonassociative tolerance development, examine a proposed physiological mechanism for associative tolerance effects, determine the extent to which associative and nonassociative morphine tolerance display cross-tolerance with the analgesic effects of other opioids, examine the development of associative and nonassociative tolerance to the analgesic effects of an opioid presumed to activate a receptor system distinct from that mediating morphine analgesia, and investigate the extent to which associative and nonassociative . tolerance to this opioid exhibit cross-tolerance with morphine. The research will provide tests of models of associative tolerance and will explore similarities and differences between associative and nonassociative tolerance phenomena across a wide range of manipulations. The studies will specifically: (1) examine the influence of environmental contingencies on tolerance development when high or low doses of morphine are explicitly paired or unpaired with a distinctive context at a short or long interdose interval; (2) explore the effects of a cholecystokinin antagonist on associative and nonassociative forms of morphine tolerance; (3) determine the cross- tolerance profiles of associative and nonassociative morphine tolerance with opioids producing analgesia through mu or kappa receptor systems; (4) investigate associative and nonassociative tolerance to the analgesic effects of a highly-specific kappa opioid; and (5) determine whether associative and nonassociative tolerance to a kappa-specific agonist display cross-tolerance with morphine. The results may have direct implications for the development of drug tolerance and dependence in addictive disorders. The data will also have relevance for the application of theories of drug conditioning to the clinical use of opioids, particularly with regard to the limits and generality of associative tolerance effects. Finally, the results will provide an evaluation of hypothetical processes subserving associative tolerance that have been posited to be functional in addictive disorders.
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