This application is for renewal of a grant to study those actions of exogenous and endogenous opioids that alter functions of the mammalian intestine, a major target organ of opioids. We have shown previously that opioids act at specific opioid receptors subtypes in the brain, spinal cord, and in the wall of the intestine to increase or decrease intestinal motility and to decrease intestinal transit. Methods have been devised for accurate assessment of opioid intestinal effects in unanesthetized animals or in vitro. The central hypothesis to be tested is that different opioid receptor subtypes in the central nervous system (CNS) and periphery mediate specific changes in gastrointestinal motility and transit. By the use of highly selective agonist and antagonist drugs, and through studies of modulating influences, the specific mechanisms by which the specific receptor subtypes affect motility and transit can be determined. Specifically, an apparent stress response (wrapping) appears to influence gastrointestinal motility without inducing analgesia in rats. The response of the intestine to wrapping stress will be examined analytically with the goal of identification of the opioid mediator responsible. The ability of alpha-MSH to inhibit analgesia and gastrointestinal responses to opioids will be determined in parallel studies in unanesthetized animals. We will determine the gastrointestinal motility (contractions) consequences of activation of central and peripheral mu, delta and kappa opioid receptor subtypes in unanesthetized animals. The neural mediators of mu opioid-induced intestinal stimulatory effects will be determined. Similarities and differences in somatic and visceral pain sensitivities to receptor-selective opioid agonists will be determined in relevant animal models. The proposed research will provide new knowledge and concepts concerning functional roles of endogenous opioid systems, will relate specific opioid receptor subtypes to specific physiological effects, and will foster the design of therapeutic agents of increased pharmacological specificity.
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