This is a resubmission of a competitive renewal application for extension of studies on the neurophysiology/neuropharmacology of microcircuits in the myenteric plexus of specialized regions of the digestive tract. These studies are designed to test the hypothesis that regional differences in organization of the microcircuits reflect specialization of the neural mechanisms for performance of region specific roles in the digestive processes of the gut as a whole. The project will finalize ongoing investigation in the rectum, continue ongoing work in the gastric antrum and progress to the pyloroduodenal and esophago-gastric junctions. Discoveries of regional specialization of myenteric neurophysiology and synaptic connectivity in the small intestine, colon, gastric corpus and rectum form the rational basis for examination of additional regions. These regional differences in the behavior of the myenteric microcircuits appear to reflect specialization of neural mechanisms for organization of the variety of specialized motor functions found in the different regions. Intracellular recording methods with dye-filled microelectrodes will be used to continue the study of neuronal electrical behavior, synaptic transmission, neuronal morphology and the neuropharmacology of relevant pharmacological agents. Microdissected preparations will be used for work in the gastric antrum and intestine. Whereas, enzymatically dissociated networks of myenteric plexus will be used for the electrophysiological studies in the pylorus, pyloro-duodenal bridge, the lower esophageal sphincter and gastric cardia. Neuropharmacological studies in the small intestinal myenteric plexus will be directed to purine nucleotides in order to finish ongoing studies of significant neuromodulatory actions of adenosine and related compounds. Neuropharmacological studies in the distal stomach will concentrate on the gastric prokinetic agents, cisapride, substituted benzamides and the motilin agonist, erythromycin. Overall, the proposed studies will result in characterization of the cellular neurophysiology, neuropharmacology and functional histoanatomy of the myenteric microcircuits responsible for control of the musculature in motor functions of the esophago-gastric junction, gastric antrum and pyloro-duodenal junction. These results are expected to improve understanding of neural determinants of motor function in the lower esophageal sphincter and in the proximal and distal stomach, as well as mechanisms of gastro-pyloro-duodenal motor coordination.
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