Enteric infections and inflammation are often associated with disturbances in gastrointestinal motility and secretion. One of the common symptoms is diarrhea. Structural and functional alterations, which occur in the enteric nervous system and interstitial cell networks in these disease states, may lead to long term disturbances in intestinal function. In order to gain an understanding of how the neural networks are programmed to regulate muscle contraction and secretion, the following specific aims will be addressed in the colon of normal guinea pigs. The first is to determine the neural pathways that coordinate muscle contraction with secretion when the stimulus is mucosal stroking. Proposed studies focus on the afferent and efferent limbs of the reflex. They include determination of the role of endogenous and exogenous 5-HT in coordinating muscle contraction and secretion, on pharmacological drugs to evoke or uncouple synaptic transmission between submucosal and myenteric ganglia and on the neurochemical and electrophysiological identity of intrinsic afferent neurons.
The second aim i s to determine the neural pathways coordinating repetitive contraction and repetitive secretion when the stimulus is histamine. Planned studies include identification of the cellular structures mediating histamine's effects and analysis of the spread of excitation through neural and interstitial cell networks. Methodologies to be used include a brush mechanism, in an in vitro whole tissue preparation, to activate intrinsic neural reflexes while recording strain gauge tension and short circuit current simultaneously. These methods will complement in situ laser confocal imaging of living tissues and will be combined with electrophysiology, morphology, immunohistochemistry and retrograde labeling of neurons to obtain a spatial analysis of calcium signals throughout the enteric nerve plexus and network of interstitial cells. These novel approaches are expected to provide new information on interactions of the enteric nervous system and interstitial cell network with muscle and epithelial cells. These studies should provide new insights into integration of two diverse functions, muscle contraction and epithelial secretion, necessary for propelling and lubricating the intestinal contents. Furthermore, they may identify potential targets for the action of therapeutic drugs used in the treatment of diarrhea.
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