Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats.
The potential relationship between stress and irritable bowel syndrome (IBS) symptomatology suggests a possible role for stress-mediating hormones, such as corticotropin-releasing factor (CRF), in the altered perception of stimuli in IBS patients. In previous studies, Wistar-Kyoto (WKY) rats with genetic indices of high anxiety demonstrated colonic hypersensitivity coupled with a high basal level of CRF within the central nervous system. In the current study we tested the hypothesis that a selective, non-peptide CRF1 receptor antagonist, antalarmin, would inhibit hypersensitivity in the WKY rat colon. Colonic sensitivity was determined by monitoring a visceromotor behavioural response during innocuous levels of colorectal distention (30 mmHg). In high anxiety WKY rats we found that antalarmin (20 mg kg-1, i.p.) significantly decreased the visceromotor response induced by colorectal distention. In a second study central administration (i.c.v.) of CRF was used to induce colonic hypersensitivity in lower anxiety Fischer 344 (F-344) rats, and in this model, antalarmin significantly inhibited the CRF-induced colonic hypersensitivity. In summary, a selective CRF1 receptor antagonist, antalarmin, inhibits colonic hypersensitivity apparent in WKY rats or in F-344 rats given a central administration of CRF. Our findings suggest that CRF1 receptor antagonism may represent a novel therapeutic approach for the treatment of IBS.
Greenwood-Van Meerveld
B
B
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA. beverley-greenwood@ouhsc.edu
Johnson
A C
AC
Cochrane
S
S
Schulkin
J
J
Myers
D A
DA
D000818:Animals; D001007:Anxiety / Q000503:physiopathology; D003106:Colon / Q000294:innervation / Q000502:physiology; D003108:Colonic Diseases / Q000188:drug therapy / Q000503:physiopathology*; D003346:Corticotropin-Releasing Hormone / Q000502:physiology; D006727:Hormone Antagonists / Q000494:pharmacology; D043183:Irritable Bowel Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D010812:Physical Stimulation; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000502:physiology*; D012018:Reflex / Q000502:physiology; D013045:Species Specificity; D000099052:CRF Receptor, Type 1
D006727:Hormone Antagonists; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C103016:antalarmin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone