Regulation of gut fluid accumulation is accomplished by mechanisms which include coordinated actions of intrinsic and extrinsic nerves to the intestine. The processes regulating luminal fluid are critical in physiological and pathological secretory conditions. We will examine the hypothesis that mucosal transport is regulated in an important way by neuropeptide influences. This hypothesis will be evaluated using a model of intestinal ion transport in vitro (which has been developed in our laboratory) together with a variety of techniques in vivo that will address the same issues, in the same species and, wherever possible, using the same compounds and protocols. This model, the mouse intestine, has characteristics different from similar portions of gut from other species. Fundamental characteristics which suggest the importance of this model are: (a) when mounted in flux chambers, the whole mouse jejunum exhibits a neurally mediated spontaneous oscillation of potential difference (PD) and short circuit current (Isc), a property not usually seen in small intestinal tissues from other species and which mimics activity in vivo; (b) the response to secretagogues is much greater in magnitude than that seen with tissues from other species, suggesting that mouse intestine may represent an appropriate model to study peripheral intestinal secretory dysfunction; (c) preliminary opioid absorption-secretion studies indicate a specific opioid receptor involvement, suggesting that the mouse tissue is ideal for the study of intestinal changes (diarrhea) associated with the opioid withdrawal syndrome, a model of neurally mediated diarrhea; and (d) the results obtained from these studies using mouse tissues in vitro, together with substantial data on gastrointestinal motility and regulation of basal fluid in mouse jejunum in vivo will allow the clearest understanding to date of neuropeptide control of the integration between ion transport and motility in the small intestine. We will carry out a physiological and pharmacological characterization of absorption-secretion processes in the mouse intestine to identify neural components regulating intestinal fluid at central or peripheral sites. The integration of data from techniques in vitro and in vivo in the same species will be important in developing an understanding of intestinal dysfunction and the relationship of neuropeptides, specifically, opioids, neuropeptide Y and CCK in these normal and disease states.
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