title: Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia.
abstract: The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF₁ and CRF₂. CRF binds with high and moderate affinity to CRF₁ and CRF₂ receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF₂ agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF₁ pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF₁/CRF₂ antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF₂ signaling in the colon dampened the CRF₁ mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF₁ system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF₁ antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF₁ antagonists. Whether the existing or newly developed CRF₁ antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.
authors.affiliation: CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Taché
authors.affiliation: CURE/Digestive Diseases Research Center, and Center for the Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, University of California Los Angeles, and VA Greater Los Angeles Healthcare System, Los Angeles, California, USA.
authors.forename: Mulugeta
authors.initials: M
authors.lastname: Million
keywords: Colonic motility, Corticotropin-releasing factor, Irritable bowel syndrome, Stress, Visceral pain