Role of corticotropin releasing factor receptor subtype 1 in stress-related functional colonic alterations: implications in irritable bowel syndrome.

The identification of the various elements of the Corticotropin Releasing Factor (CRF) system including the characterisation of four mammalian CRF-related peptides, the cloning of two CRF receptor subtypes 1 and 2 (CRF1; CRF2) and the development of selective CRF1 receptor antagonists has allowed investigators to establish an important role for the CRF signalling pathways in coordinating the physiological and behavioural components of the stress response. In particular, compelling preclinical evidence showed that both central and peripheral injection of CRF mimicked stress-induced stimulation of colonic motility, transit, defaecation, and occurrence of diarrhoea along with degranulation of mast cells, and increased secretion of prostaglandin E2, mucus, and ionic permeability. Central CRF also increased abdominal pain from colorectal distention in rats and peripheral CRF reduced pain threshold to colonic distention and increased colonic motility in humans. Non-selective CRF antagonists for receptors 1 and 2 and selective CRF, antagonists inhibit exogenous (central or peripheral) CRF, and acute stress-induced stimulation of colonic motor and secretory function and visceral hyperalgesia. CRF1 receptors mediate stress-related anxiogenic and depression-like behaviours in rodents and CRF, antagonist reduced depression in a phase II clinical trial. These findings lend support to the hypothesis that hyperactivation of CRF1 receptors may contribute to the co-morbidity of anxiety and depression and irritable bowel syndrome. Targeting these pathways with selective CRF1 antagonists may be a novel therapeutic venue for diarrhoea-predominant IBS patients.