The longterm goals are to understand the relationship between intestinal ion transport and the submucosal enteric neurons which play a key role in controlling this important homeostatic function. A multi-technique approach toward this goal will be used, combining intracellular recording and filling with dyes of submucosal neurones, anterograde and retrograde labelling of mucosa-to-submucosa projections, immunohistochemistry, selective denervations and tight-seal, patch clamp recording techniques. These techniques will be used to: (1) identify patterns of neuronal circuitry involving mucosal reflexes, (2) identify cellular mechanisms of neuronal excitation by putative neurotransmitters, in particular 5-HT3 receptor activation which mediates fast (ms time range) excitation and activation of receptors by substance P, muscarine, adenosine and vasoactive intestinal polypeptide (VIP) which mediate slow (s to min time range) excitation, (3) identify mechanisms of neuronal inhibition, specifically the mechanisms by which somatostatin and alpha2-adrenoceptors increase activity of single potassium channels and inhibit activity of single calcium channels. These studies will contribute significantly to basic research areas of physiology of the gastrointestinal tract as well as cellular neurophysiology in general. These studies have direct pharmacological and clinical relevance for drug use and drug development of anti-emetics to prevent chemotherapy-induced nausea and vomiting. These studies will help to identify submucosal neurones which participate in the pathophysiology of enterotoxins, such as cholera and salmonella.
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