Our laboratory has developed neuropharmacologic evidence that peptides in the brain exerts powerful influence on gastric secretion and motility and are potentially important physiologic regulator of gastric functions. The overall objective of the work described in this proposal is to increase our knowledge on the brain regulation of gastric secretory function. Selecting neuropeptides that we previously demonstrated to act within the brain to stimulate (thyrotropin-releasing hormone, TRH) or to inhibit (bombesin, interleukin-1beta, IL-1beta) gastric secretory and motor function, the specific aims will be (1) to further localize and map specific brain sites of action by monitoring changes in gastric secretion (acid, histamine, serotonin) evoked by microfusions of these peptides in specific hypothalamic, amygdalar and medullary structures, (2) to study neural pathways involved in mediating peptide action by monitoring changes in efferent and afferent activity in nerve fibers innervating the stomach and recording extracellular activity from identified neurons in the dorsal vagal complex, (3) to further characterize CNS and peripheral neurotransmitters or hormones mediating peptide action using pharmacological and surgical approaches, and (4) to evaluate the physiological role of medullary TRH in the vagal stimulation of gastric function and IL-1beta endotoxin-induced gastric hyposecretion. Gastric acid secretion will be measured in pylorus-ligated rats or through gastric fistula. Blood withdrawn from the hepatic portal vein will be essayed for histamine and for serotonin levels. Electrophysiological recording of the efferent and afferent nerve activity will be performed using microdissection techniques to isolate single or multi-unit fibers from the ventral gastric branch of the vagus and splanchnic nerve. The physiological role of these peptides will be assessed by (1) measuring variations in TRH gene expression in medullary nuclei (TRH mRNA) in response to stimuli activating parasympathetic outflow to the stomach, or release of Il-1beta into the CSF in response to endotoxin, (2) using passive immunization (Fab fragment of monoclonal antibody against TRH microinjected into sites of vagal outflow to the stomach and infection of IL-1beta antibody into the CSF or peripherally prior to endotoxins-induced gastric hyposecretion) and (3) testing biologically active antagonists recently developed for their ability to prevent central action of bombesin. Such studies will yield substantive information on brain nuclei that respond to peptides and are involved in regulating gastric secretion (acid, histamine, serotonin) and autonomic outflow to the stomach. We will test a model that includes major role of these peptides in brain regulation of gastric function in health and disease.
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