Thyrotropin-releasing hormone (TRH) and somatostatin are among the peptides which induce a vagal-dependent stimulation of gastric function when injected into the dorsal motor nucleus (DMN) of the vagus. Results provided during the last grant period indicate that activation of raphe pallidus containing TRH cell bodies projecting to the DMN induces a vagal cholinergic-dependent stimulation of gastric function through TRH action in the DMN. In addition, the vagal cholinergic gastric hyperemic response to central injection of TRH was shown to be mediated by capsaicin- calcitonin gene-related peptide (CGRP) and nitric oxide dependent mechanisms. The objective of the current proposal is to characterize the mechanisms of action and physiological roles of medullary TRH and SST in the vagal regulation of gastric function.
The specific aims of this application are (1) to define the roles and regulation of TRH/5-HT projections from caudal raphe nuclei to the DMN in vagally-mediated stimulation of gastric function, particularly as it relates to the gastric responses to sham feeding, 2-deoxy-D-glucose, and mild irritants; (2) to prove that medullary TRH-induced vagal cholinergic gastric responses are mediated or modulated by efferent function of capsaicin-sensitive afferent terminals releasing CGRP; (3) to characterize, in the dorsal vagal complex, SST receptor subtypes distribution and action to influence gastric function.
These aims will be achieved by combined methods of approach: neuropharmacological (microinjections of TRH antibody, selective SST ligands), neurohistochemical (c-fos expression in medullary nuclei as a marker of neuronal activity), molecular (TRH gene expression in caudal raphe in response to stimuli activating vagal outflow), electrophysiologic (recording of the afferent and efferent gastric vagal activity of celiac afferents) and biochemical (CGRP release). Experiments will be performed in conscious or anesthetized rats to monitor gastric acid secretion, motility and mucosal blood flow and/or resistance of the mucosa to gastric injury. These studies will advance knowledge on (1) neuroanatomical circuitry and biochemical coding through which vagal outflow is regulated in the medulla; (2) the physiological role of TRH and 5-HT contained in the caudal raphe-DMN pathways; (3) the mechanism involved in the interaction between vagal efferent activity and recruitment of """"""""efferent function"""""""" of capsaicin-sensitive afferents that have biological relevance in mediating the gastric response to vagal activation; (4) the mechanisms of action of SST at medullary sites influencing vagal outflow.
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