The characterization of corticotropin releasing factor (CRF) and more recently the

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. 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 Nutlin 3b 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 Nutlin 3b animals. These findings implicate CRF1 receptors in C1orf215 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. and form being found only in human Nutlin 3b amygdala (Kostich were injected icv under short enflurane anesthesia with either vehicle the selective CRF1 antagonist NBI-35965 or the selective CRF2 antagonist … Table 1 Acute stress-induced activation of colonic motor function: inhibition by pretreatment with CRF antagonists in experimental animals Central CRF and Nutlin 3b restraint stimulate colonic motor function through similar autonomic pathways Convergent studies indicate that central CRF-induced sustained stimulation of colonic motor activity is neurally mediated through the activation of parasympathetic cholinergic pathways and occurs independently from the activation of the HPA axis in rats. Transneuronal labeling showed that the PVN and LC/subLC/Barrington complex send direct projections to the intermediolateral column at the S1 segment of the rat sacral spinal cord that provides parasympathetic innervation of the colon (Vizzard et al. 2000 Taché 2002 Pharmacological and surgical interventions showed that the colonic motor stimulation (motility transit defecation) in response to centrally injected CRF was unchanged after hypophysectomy adrenalectomy noradrenergic blockade and by opiate antagonist but attenuated by vagotomy and abolished by ganglionic blockade and atropine (Lenz Nutlin 3b et al. 1988 Gué et al. 1991 M?nnikes et al. 1992 1993 1993 The icv CRF-induced defecation was also blocked by the neurokinin-1 (NK-1) antagonist TAK-637 and by the 5-HT3 antagonists ramasetron and azasetron (Miyata et al. 1998 Okano et al. 2001 These data suggest that the parasympathetic activation by icv CRF results in colonic release of substance P acting on NK-1 receptors as well as serotonin activating 5-HT3 receptors. Parallel studies established that pathways that mediate restraint stress-induced colonic motor response are similar to those recruited by icv injection of CRF. The stimulation of colonic transit and defecation by restraint were not modified by hypophysectomy adrenalectomy naloxone indomethacin or bretylium but were attenuated by vagotomy and abolished by ganglionic blockade atropine and NK-1 or 5-HT3 antagonists (Lenz & Druge 1990 Castagliuolo et al. 1996 Miyata et al. 1998 Okano et al. 2001 Role of peripheral CRF receptors in stress-related stimulation of colonic motor and epithelial functions CRF- and urocortin 1 injected peripherally stimulate colonic function The role of peripheral CRF signaling pathways in the colonic response to stress has been recently reviewed (Taché & Perdue 2004 CRF and urocortin 1 injected intraperitoneally (i.p.) or intravenously (i.v.) in conscious rats induced propulsive motor events as shown by the occurrence of clustered spike bursts of long duration in the cecum and proximal colon reduction of large intestine and distal colonic transit time defecation and at the highest doses watery diarrhea in rats and mice (Williams et al. 1987 Lenz et al. 1988 1988 Castagliuolo et al. 1996 Maillot et al. 2000 2003 Gabry et al. 2002 Martinez et al. 2002 2004 Million et al. 2002 Saunders et al. 2002 Likewise in humans i.v. CRF increased motility in the descending colon and IBS patients had a greater response than healthy volunteers (Fukudo et al. 1998 In addition to stimulating colonic motor function i.v. or i.p. CRF increases colonic mucin rat mast cell protease II and prostaglandin 2 (PGE2) release ion secretion.