CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome

Authors

  • Y Taché,

    Corresponding author
    1. CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA, U.S.A.
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  • V Martinez,

    1. CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA, U.S.A.
    2. Integrative Pharmacology-Gastrointestinal Biology, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden
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  • L Wang,

    1. CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA, U.S.A.
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  • M Million

    1. CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences and Woman's Health, West Los Angeles VA Medical Center, Division of Digestive Diseases, Department of Medicine, University of California Los Angeles, Los Angeles, CA, U.S.A.
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CURE, Bldg 115, Room 117, VA Greater Los Angeles Health Care System, 1130 Wilshire Blvd, Los Angeles, CA 90073, U.S.A. E-mail: ytaché@ucla.edu

Abstract

  • The characterization of corticotropin releasing factor (CRF) and, more recently, the discovery of additional CRF-related ligands, urocortin 1, urocortin 2 and urocortin 3, the cloning of two distinct CRF receptor subtypes, 1 (CRF1) and 2 (CRF2), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress. Activation of brain CRF1 receptor signaling pathways is implicated in stress-related endocrine response and the development of anxiety-like behaviors.

  • Compelling evidence in rodents showed also that both central and peripheral injection of CRF and urocortin 1 mimic acute stress-induced colonic response (stimulation of motility, transit, defecation, mucus and watery secretion, increased ionic permeability and occurrence of diarrhea) in rodents. Central CRF enhances colorectal distention-induced visceral pain in rats. Peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans.

  • Nonselective CRF1/CRF2 antagonists and selective CRF1 antagonists inhibit exogenous (central or peripheral) CRF- and acute stress-induced activation of colonic myenteric neurons, stimulation of colonic motor function and visceral hyperalgesia while selective CRF2 antagonists have no effect. None of the CRF antagonists influence basal or postprandial colonic function in nonstressed animals.

  • These findings implicate CRF1 receptors in stress-related stimulation of colonic function and hypersensitivity to colorectal distention. Targeting CRF1-dependent pathways may have potential benefit against stress or anxiety-/depression-related functional bowel disorders.

British Journal of Pharmacology (2004) 141, 1321–1330. doi:10.1038/sj.bjp.0705760

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