CRF is a 41 amino acid peptide originally characterized from the hypothalamus. CRF-like immunoreactivity and receptors are also localized in extra-hypothalamic tissues including the brainstem, spinal cord, sympathetic ganglia, adrenals and gastrointestinal (GI) tract. Central injection of CRF induces similar alterations of GI function as stress exposure. Results obtained with the CRF antagonist, alpha-helical CRF9-41, indicates that CRF may be a key signal coordinating the endocrine, behavioral, cardiovascular and GI responses to stress. The objectives of this application are (1) to gain insight on central mechanisms through which CRF alters GI motor function and (2) to further establish the role of endogenous CRF in psychological and surgical stress-related alterations of gastric and colonic motor activity. To achieve aim 1, we will (a) localize brain and spinal responsive sites to CRF using microinjection technique, (b) establish whether there is a correlation between behavior and GI responses at these sites, and (c) assess electrophysiologically the effects of central CRF on vagal and splanchnic efferent activity and (d) whether CRF interacts with TRH at medullar sites regulating vagal outflow to the stomach.
The aim 2 will be pursued by investigating by the neuropharmacological (CRF receptor antagonist) and molecular biology (in situ hybridization of CRF mRNA) approaches the role of central CRF in psychological stress-induced alterations of GI transit and of central and peripheral CRF in surgical stress-induced delay in gastric emptying. Mapping of brain responsive sites will be performed in conscious rats chronically implanted with guide cannula and gastric and colonic transit will be assessed using markers delivered through chronically implanted catheters. Colonic and gastric motility will be monitored by implanted strain gauges. Psychological stress will be induced by passive avoidance to water and surgical stress by laparotomy followed by cecum exteriorization. These studies will advance knowledge on (1) brain sites regulating gastric and colonic motor function, (2) central mechanisms of CRF action on GI motility, (3) the physiological role of central CRF in mediating psychological stress induced alterations of GI transit and central pathways involved, and (4) mechanisms underlying postoperative gastric stasis. Overall, these studies will provide insight on neuroanatomical and chemical substrata involved in stress-related alterations of GI motor function and may have important implications in the understanding and treatment of postoperative ileus and the irritable bowel syndrome.
Showing the most recent 10 out of 158 publications
