EXTRINSIC CONTROL OF GASTROINTESTINAL MOTILITY

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Although peripheral autonomic ganglia are important in the maintenance of normal gastrointestinal functions, the mechanisms of ganglion cell excitability, transmission and interconnectedness between the ganglia and their target organs are as yet imperfectly understood. The overall objectives of this proposal are: (1) to elucidate in guinea pigs, mice and cats, the range of mechanisms by which prevertebral ganglia control motor activity of the colon; and (2) the basic electrophysiology underlying excitability and chemical transmission in intrapancreatic ganglia, a hitherto unexplored area of gastroenterology. Investigations in the inferior mesenteric ganglion (IMG) are designed to answer the following questions. First, do axon collaterals of spinal afferent capsaicin- sensitive nerves mediate a peripheral, visceral sensory-autonomic reflex by releasing SP-, NKA- and CGRP-LI in the IMG during colonic distension? Second, do central preganglionic peptide containing nerves synapsing in the IMG gate distension-induced release of SP-, NKA- and CGRP-LI? Third, do colonic myenteric VIP-containing neurons projecting to sympathetic neurons in the IMG release VIP during colonic distension? Fourth, what is the functional importance of GABA-containing colonic afferents? And, fifth, what is the nature of the colonic mechanoreceptor unit which mediates peripheral reflex activity and where is it located in the colon wall? Investigations in intrapancreatic ganglia are designed to answer the following questions. First, are there differences in electrophysiological characteristics between intrapancreatic neurons in the head and tail regions of the pancreas? Second, do CCK peptides, VIP and 5-HT participate in intrapancreatic synaptic events? And third, are gastroduodenal myenteric neurons that send their axonal projections to intrapancreatic ganglia activated by distension and/or intraluminal acidity? Intracellular electrophysiological techniques will be combined with radioimmunological, chromatographic and quantitative radiodensitometric thin-layer chromatographic techniques. It is hoped that these studies will shed light on disorders of colonic motility in humans. The presence of functional GABA receptors in peripheral autonomic ganglia makes it very likely that anxiolytic drugs like the benzodiazepines very likely affect gastrointestinal motility in patients. Studies on intrapancreatic ganglia will provide a better understanding of their physiological importance thereby providing insights into pancreatic function of the transplanted organ.