Convergent neuroanatomical and biological reports implicate corticotropin releasing factor ( 41 amino-acid peptide, as a key mediator in the endocrinological, behavioral. and autonomic responses stress. Results obtained during the last grant period provided evidence in rats that central CRY mediate psychological, and immune (interleukin- 1beta, IL-l) stress-induced alterations of GI motor function namely the delay in gastric emptying and stimulation of colonic transit in rats. The overall goals are to define the neuroanatomical substrata underlying C.F. and IL-1 actions in the brain to induce alterations of gastric an autonomic motor function and their implications at these sites to the stress response in rats. The objectives of this application are to establish that (l) C.F. acts in the locus coeruleus to activate noradrenergic neurons an stimulate colonic motor function through sacral parasympathetic cholinergic pathways. (2) endogenous C.F. released by environmental stress in the locks coeruleus activates neurons and stimulates colonic motor function; (3) C.F. in the paraventricular nucleus of the hypothalamus has opposite effects on preganglionic parasympathetic neurons in medulla and sacral spinal cord. leading to decreased gastric vagal outflow and increased cholinergic input to the colon (4) C.F. in the paraventricular nucleus of the hypothalamus accounts for the gastric stasis induced by central and peripheral injection of IL-1beta.
These aims will be achieved by combined neuropharmacological (microinjection of C.F. and/or antagonist or neurotoxins at these sites), neurohistochemical (c-fos expression in the brain and sacral spinal cord as a marker of neuronal system activity combined with double labelling of noradrenergic or C.F. neurons) and electrophysiological (recording o efferent activity in gastric vagus) methods of approach. All experiments will be performed in conscious rats with chronically implanted guide cannulas for microinjections and gastric and colonic catheters to deliver markers allowing measurement of transit except electrophysiological studies performed in rats under halothane anesthesia. These studies will advance knowledge on (I) brain sites regulating gastric and colonic motor function. (2) neuroanatomical and neurochemical circuitry through which central C.F. and IL-lbeta alter GI motor function. (3) brain sites and neurotransmitters involved in regulating parasympathetic outflow to the stomach and the colon, (4) IL-1 as mediator in the interaction between the immune system and gastric function. Overall, these studies will enhance knowledge on the pathways through which psychological and immunological stress induce alterations of GI motor function, and they may also have implications in stress related exacerbations of human irritable bowel syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK033061-14
Application #
2734022
Study Section
Special Emphasis Panel (ZRG4-GMA-1 (01))
Program Officer
May, Michael K
Project Start
1983-12-01
Project End
2000-06-30
Budget Start
1998-07-15
Budget End
1999-06-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Karasawa, Hiroshi; Yakabi, Seiichi; Wang, Lixin et al. (2014) Orexin-1 receptor mediates the increased food and water intake induced by intracerebroventricular injection of the stable somatostatin pan-agonist, ODT8-SST in rats. Neurosci Lett 576:88-92
Duboc, Henri; Taché, Yvette; Hofmann, Alan F (2014) The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 46:302-12
Taché, Yvette; Adelson, David; Yang, Hong (2014) TRH/TRH-R1 receptor signaling in the brain medulla as a pathway of vagally mediated gut responses during the cephalic phase. Curr Pharm Des 20:2725-30
Stengel, Andreas; Rivier, Jean; Taché, Yvette (2013) Central actions of somatostatin-28 and oligosomatostatin agonists to prevent components of the endocrine, autonomic and visceral responses to stress through interaction with different somatostatin receptor subtypes. Curr Pharm Des 19:98-105
Wang, Lixin; Stengel, Andreas; Goebel-Stengel, Miriam et al. (2013) Intravenous injection of urocortin 1 induces a CRF2 mediated increase in circulating ghrelin and glucose levels through distinct mechanisms in rats. Peptides 39:164-70
Stengel, A; Mori, M; Tache, Y (2013) The role of nesfatin-1 in the regulation of food intake and body weight: recent developments and future endeavors. Obes Rev 14:859-70
Stengel, Andreas; Rivier, Jean; Taché, Yvette (2013) Modulation of the adaptive response to stress by brain activation of selective somatostatin receptor subtypes. Peptides 42:70-7
Yuan, Pu-Qing; Wu, S Vincent; Tache, Yvette (2012) Urocortins and CRF type 2 receptor isoforms expression in the rat stomach are regulated by endotoxin: role in the modulation of delayed gastric emptying. Am J Physiol Gastrointest Liver Physiol 303:G20-31
Larauche, Muriel; Mulak, Agata; Taché, Yvette (2012) Stress and visceral pain: from animal models to clinical therapies. Exp Neurol 233:49-67

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