This application is for competitive renewal of an established, productive project directed at understanding actions of opioids on gastrointestinal functions. Work supported by this grant in the past provided convincing evidence for brain mediation of some gastrointestinal responses to opioids, identified the spinal cord as one site of opioid action with consequences for gastrointestinal regulation, and provided differentiation of mu, delta and kappa antitransit effects. Recent studies in our laboratory provide evidence that opioids produce a variety of patterns of effects on gastrointestinal motility (contractions) and transit (propulsion). The proposed experiments will test the hypothesis that the specific patterns of motility effects generated by opioids depend on (A) anatomical sites affected (CNS, peripheral, direct) , (B) types of opioid receptors involved at each site (mu, delta, kappa) , (C) region of the gastrointestinal tract studied (stomach, small intestine, cecum and colon), (D) pharmacokinetic properties of the agonists (peptide vs. alkaloid) and therefore on route of administration, (E) unique dose-response relationships, and (F) that endogenous central and peripheral opioids participate in acute and chronic stress responses of the gastrointestinal tract. Moreover, evidence is put forward that certain non-opioid peptides play mediator roles in gastrointestinal responses to opioids. We will employ highly mu, delta and kappa selective opioid agonists and antagonists to determine precisely the effects of opioids on motility after central and peripheral administration and in naive and tolerant animals. We will also determine the relationship between gastrointestinal contractile activity and gastrointestinal transit (propulsion). These data will provide new insight into the actions of opioids with gastrointestinal consequences, will help define brain-gut interactions, and will provide information about regulatory roles of important classes of neuropeptides.
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