This research will investigate behavioral and pharmacological variables that modify the development and expression of tolerance to the actions of opioid agonists and mixed agonist-antagonists. The experimental methods of behavioral pharmacology will be used to identify ways in which the tolerance and dependence produced by acute or chronic opioid administration can be manipulated. The behavioral end-points assessed will include 1) ongoing rates and patterns of schedule-controlled behavior, 2) the discriminative stimulus properties of morphine, and 3) analgesia as assessed in a thermal nociception assay. Specific experiments will assess the development and degree of tolerance to the rate- altering effects of etorphine, morphine, and buprenorphine during chronic injections or osmotic infusions of each opioid. Parallel experiments will assess the development and degree of analgesic tolerance and behavioral dependence during identical chronic administration regimens. Other experiments will evaluate the behavioral sequelar of long-term administration of the opioid antagonist naltrexone. A third group of experiments will evaluate the contributions of the behavioral demands imposed by the reinforcement schedule to the development and maintenance of tolerance to the rate-altering and discriminative stimulus properties of morphine. A final group of experiments will assess changes in the discriminative stimulus profile of morphine during chronic administration of opioid agonists, antagonists, and mixed agonist-antagonists. Pharmacotherapies are gaining increasing importance in the treatment of human drug abuse. Pre-clinical identification of the behavioral consequences of long-term opioid administration, and of the ways such consequences can be modified by pharmacological and psychological factors, may have important implications for our understanding of both tolerance processes in general and the factors underlying opioid abuse.
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