Research efforts in medicinal chemistry have produced opioid and nonopioid analgesics which may provide effective pain relief with reduced dependence potential. It is our objective to examine the analgesic effects of a number of these compounds with emphasis on agonists presumed to have activity at mu or kappa opioid receptor types. Analgesic activity will be assessed with 2 procedures, the squirrel monkey shock titration procedure and a newly developed thermal discrimination procedure in rats. In addition, studies will be carried out in which the intensity of the nociceptive stimulus (shock or heat) is manipulated in order to determine 1) the extent to which the effects of mu or kappa agonists depend on stimulus intensity and 2) whether analgesic effects might be revealed for less efficacious compounds at lower stimulus intensities. For comparison, we will also examine the effects of several mu and kappa opioid agonists on schedule- controlled behavior. These investigations will be carried out in squirrel monkeys, rats and pigeons so that differences in drug effects between species can be examined. In addition, the discriminative stimulus properties of mu and kappa opioid agonists will be investigated in rats and pigeons. In all of these studies, emphasis will be placed on the relationship between the behavioral effects of opioid agonists and the mediation of their effects through different opioid receptor types. In order to draw such relationships, opioid agonists will be examined alone, in combination with opioid antagonists and in animals made tolerant to mu or kappa agonists. Comparisons will then be made on the basis of 1) differing behavioral profiles and potency relationships among the opioid agonists 2) the potency of opioid antagonists in attenuating the effects of these agonists and 3) the occurrence of cross tolerance among them.
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