Stress and corticotropin-releasing factor (CRF) exert a profound effect on colon secreto-motor function, primarily through CRF1 receptors. The physiological role of CRF2 in the colonic response to stress is unknown. Preliminary data show that first, pharmacological activation of peripheral CRF2 prevents CRF1-mediated stressor CRF-induced colonic enteric neuron activation and diarrhea while blockade or deletion of CRF2 enhances the colonic motor response to stress. Second, CRF1 activation enhances visceral pain response while CRF2 activation prevents capsaicin induced primary culture lumbosacral DRG neurons Ca2+ transients. Third, CRF causes less cAMP production in cells that express both CRF1/CRF2 than in cells that expresses only CRF1. Based on these key observations, we hypothesize that in rodents, peripheral CRF2 serves as a stress-coping signal that halts stress-induced colonic motility and visceral hyperalgesia through a direct and indirect action on peripheral target cells.
Specific aim 1 will establish the physiological role of CRF2 as a stress-coping mechanism in acute and chronic stress-induced colonic motor response, through inhibition of colonic enteric neurons. This will be achieved by blockade or deletion of CRF2 as well as by blocking neurotransmitter pathways and by demonstrating that stress and extrinsic nerve stimulation induce CRF ligand release in vivo and in vitro.
Specific aim 2 will test that CRF2 prevents CRF1 mediated acetylcholine release and promotes inhibitory neurotransmitters release in longitudinal muscle myenteric plexus (LMMP) tissue and primary colonic myenteric neuron culture. The putative CRF1-CRF2 interaction in native and transfected cells will be studied to gain insight on the CRF1-CRF2 signaling cross talk.
Specific aim 3 will determine whether activation of peripheral CRF2 inhibits stress-induced visceral pain sensitization through the inhibition of pelvic afferents and lumbosacral DRG neurons by performing functional, electrophysiological and molecular assays in vivo in isolated colonic afferent preparation and in vitro DRG neurons. The elucidation of the physiological role and mechanisms through which peripheral CRF2 dampens stress- and CRF-related colonic omotor alterations and visceral hypersensitivity will have important clinical implications in functional disorders such as irritable bowel syndrome, where a link between stress, CRF1 signaling pathway and symptoms are increasingly recognized. Public Health Relevance: The proposed study aims at establishing that CRF2 receptor signaling in the colon functions as a stress adaptation system to maintain colonic motor and pain response homeostasis. The study has relevance to gut diseases that are triggered or exacerbated by stress, including IBS. The elucidation of the effects and mechanisms through which peripheral CRF2 activation dampen stress- or CRF-related increases in colonic motor activity and visceral pain will have important clinical implications for functional gut diseases such as IBS, for which a link between stress and symptoms are increasingly recognized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078676-03
Application #
7899789
Study Section
Clinical and Integrative Gastrointestinal Pathobiology Study Section (CIGP)
Program Officer
Hamilton, Frank A
Project Start
2008-08-15
Project End
2013-07-31
Budget Start
2010-08-01
Budget End
2011-07-31
Support Year
3
Fiscal Year
2010
Total Cost
$265,073
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Tache, Yvette; Larauche, Muriel; Yuan, Pu-Qing et al. (2018) Brain and Gut CRF Signaling: Biological Actions and Role in the Gastrointestinal Tract. Curr Mol Pharmacol 11:51-71
Wang, Lixin; Jacobs, Jonathan P; Lagishetty, Venu et al. (2017) High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats. Am J Physiol Regul Integr Comp Physiol 313:R473-R486
Moussaoui, Nabila; Jacobs, Jonathan P; Larauche, Muriel et al. (2017) Chronic Early-life Stress in Rat Pups Alters Basal Corticosterone, Intestinal Permeability, and Fecal Microbiota at Weaning: Influence of Sex. J Neurogastroenterol Motil 23:135-143
Duboc, Henri; Tolstanova, Ganna; Yuan, Pu-Qing et al. (2016) Reduction of epithelial secretion in male rat distal colonic mucosa by bile acid receptor TGR5 agonist, INT-777: role of submucosal neurons. Neurogastroenterol Motil 28:1663-1676
Moussaoui, Nabila; Larauche, Muriel; Biraud, Mandy et al. (2016) Limited Nesting Stress Alters Maternal Behavior and In Vivo Intestinal Permeability in Male Wistar Pup Rats. PLoS One 11:e0155037
Million, M; Larauche, M (2016) Stress, sex, and the enteric nervous system. Neurogastroenterol Motil 28:1283-9
Taché, Yvette; Million, Mulugeta (2015) Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia. J Neurogastroenterol Motil 21:8-24
Akiba, Yasutada; Kaunitz, Jonathan D; Million, Mulugeta (2015) Peripheral corticotropin-releasing factor receptor type 2 activation increases colonic blood flow through nitric oxide pathway in rats. Dig Dis Sci 60:858-67
Mulak, Agata; Larauche, Muriel; Biraud, Mandy et al. (2015) Selective agonists of somatostatin receptor subtype 1 or 2 injected peripherally induce antihyperalgesic effect in two models of visceral hypersensitivity in mice. Peptides 63:71-80

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