Enteric excitatory and inhibitory motor neurons both importantly contribute to modulation of colonic motility and are central to the process of peristalsis. The proposed experiments will investigate how these motor neurons modulate the ongoing electrical and contractile activity which occurs in the circular muscle layer of the dog and human colon. By using various antagonists we will characterize the electrical and contractile events associated with: I. Cholinergic excitatory neuronal responses, II. Inhibitory neuronal responses and III. Non-cholinergic excitatory neuronal responses. We hypothesize that ACh and tachykinins (TK) both contribute to excitatory neural responses and that NO, VIP and ATP all contribute to inhibitory neural responses. Direct evidence for release of TKs, and VIP will be provided from release studies. Since the circular muscle layer is functionally complex, segments of the intact layer will be compared to subsections of this layer which contain either a single pacemaker/plexus region or no plexus/pacemaker region. In this way we will determine the extent to which enteric neurons functionally innervate the various subsections and quantitate the manner which they modulate mechanical and electrical activity in these regions. This information will be used to construct a model of how excitatory and inhibitory motor neurons modulate the activity of the intact circular muscle layer. We hypothesize that both excitatory and inhibitory motor neurons functionally innervate both pacemaker and non-pacemaker regions of the circular muscle layer and that the net effect of motor neurons on colonic motility is the sum of the electrical and mechanical changes which they produce in both pacemaker as well as non-pacemaker regions. While much is known of the electrical and contractile properties of the canine colon, our knowledge of the human muscle is less complete. By comparing responses in these two species we will therefore not only enhance our knowledge of the human muscle but also provide a means for assessing the degree to which the canine colon is a useful model for human colonic function. Understanding in more detail the norma physiology of the colon may also provide important information to improve such conditions as irritable bowel syndrome and Hirschsprung's disease as well as aiding in the development of new treatment for more common maladies such as constipation and diarrhea.
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