The activation of corticotropin-releasing factor (CRF) receptor subtype 1 (CRF1) plays an important role in the anxiogenic and endocrine responses to stress. We previously demonstrated that central CRF1 mediates exogenous CRF- and psychological stress-induced stimulation of colonic transit. Preliminary data also indicate CRF1 involvement in stress-related visceral hypersensitivity and that CRF2 ligands inhibit gastric emptying similarly as stress does. The overall objectives are to establish the mechanisms through which brain activation of CRF2 alters gastric motor function and CRF1, visceral hypersensitivity and their implication in the gut response to stress.
The first aim will characterize the hypothalamic sites of action of newly discovered selective CRF2 ligands to inhibit gastric motility and the role of brain CRF2 in the gastric response to systemic and psychological stress.
The second aim will test the hypothesis that CRF2 receptor expressed in the nodose ganglia and the dorsal vagal complex/area postrema leads to alterations of gastric and sphincter contractile activity through modulation of vagal afferent and efferent activity. The last aim will establish that CRF1 is involved in stress-related hypersensitivity to colorectal distention through activation of locus coeruleus and paraventricular nucleus neurons. New advances related to the discovery in the brain of two peptides, urocortin II and urocortin III with selective affinity to CRF2 receptors along with the recent development of a selective potent CRF2 antagonist, astressin-2B, selective CRF1 agonists, and CRF1 and CRF2 knockout mice will provide new means to achieve the objectives. Electrophysiological (simultaneous dual gastric vagal afferent and efferent recording and locus coeruleus neuronal activity), neuroanatomical (Fos immunohistochemistry, in situ hybridization and RT-PCR, retrograde tracing and double labeling), neuropharmacological (brain microinjection) and functional (simultaneous recording of gastric and sphincter motility by a novel sonomicrometry method, and gastric and colonic transit) will be used to perform the aims. Unraveling the CRF receptor subtypes and brain pathways underlying stress-induced alterations of gut motor function and viscerosensitity will have important implications in the understanding of stress-related gut alterations and possible implications in functional bowel diseases (irritable bowel syndrome and dyspepsia).
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