Corticotropin-releasing factor 1 receptor-mediated mechanisms inhibit colonic hypersensitivity in rats

Neurogastroenterol Motil. 2005 Jun;17(3):415-22. doi: 10.1111/j.1365-2982.2005.00648.x.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anxiety / physiopathology
  • Colon / innervation
  • Colon / physiology
  • Colonic Diseases / drug therapy
  • Colonic Diseases / physiopathology*
  • Corticotropin-Releasing Hormone / physiology
  • Hormone Antagonists / pharmacology
  • Irritable Bowel Syndrome / drug therapy
  • Irritable Bowel Syndrome / physiopathology*
  • Physical Stimulation
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Rats
  • Rats, Inbred F344
  • Rats, Inbred WKY
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors
  • Receptors, Corticotropin-Releasing Hormone / physiology*
  • Reflex / physiology
  • Species Specificity

Substances

  • Hormone Antagonists
  • Pyrimidines
  • Pyrroles
  • Receptors, Corticotropin-Releasing Hormone
  • antalarmin
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone