The research proposed is designed to provide a more quantitative measure of the effects of opioid agonists, antagonists, and mixed agonist-antagonists on both mu- and kappa-induced opioid dependence in rhesus monkeys and pigeons. In monkeys, much data has been accumulated on this issue using observations of behavioral changes following administration of opioids in morphine- and U-50,488- (a kappa agonist) dependent subjects. This procedure has several drawbacks, including dependence on trained observers, subjective reports of withdrawal signs, use of rating scales, and the need for high morphine doses to produce strong dependence. In the current proposal, monkeys will be trained to discriminate the administration of naltrexone from that of saline using a standard drug discrimination procedure. Naltrexone will serve as an indicator of morphine withdrawal in a group of monkeys receiving relatively low doses of morphine chronically during training and testing of the naltrexone cue, and will serve as an indicator of U-50,488 withdrawal in a group of monkeys receiving chronic U-50,488 during this time. The capacity of this procedure to produce data relevant to the modification of withdrawal has been demonstrated well by prior studies in pigeons. Pigeons will be trained to discriminate naltrexone from both morphine and saline to allow parametric evaluation of the effects of drugs on withdrawal from each of three different morphine maintenance doses. These series of studies should be helpful in assessing drugs for potential use in the treatment of opioid dependence, for assisting in the classification of currently available and newly developed opiate analgesics, as well as having considerable interest to basic scientists in the field of opioid pharmacology and behavioral pharmacology.
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