Submitted on February 27, 2009
Revised on April 27, 2009
Accepted on April 28, 2009
Cortagine, a CRF1 agonist, induces stress-like alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways
Muriel Larauche1*, Guillaume Gourcerol2, Lixin Wang3, Karina Pambukchian3, Stefan Brunnhuber3, David W. Adelson4, Jean Rivier5, Mulugeta Million3, and Yvette F. Tache6
1 UCLA - Center for Neurobiology of Stress
2 University of Rouen
3 UCLA
4 VAGLAHS
5 3The Clayton Foundation Laboratories for Peptide Biology
6 University of California, Los Angeles
* To whom correspondence should be addressed. E-mail: mlarauche{at}mednet.ucla.edu.
Corticotropin-releasing factor (CRF) 1 receptor (CRF1) activation in the brain is a core pathway orchestrating the stress response. Anatomical data also support the existence of CRF signaling components within the colon. We investigated the colonic response to intraperitoneal (i.p.) injection of cortagine, a newly developed selective CRF1 peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored using a modified miniaturized pressure transducer catheter in adult conscious male SD rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared to vehicle, cortagine (10 µg/kg, i.p.) significantly decreased the distal colonic transit time by 45% without affecting gastric transit, increased distal and transverse colonic contractility by 35.6% and 66.2% respectively, induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the 1st h post injection while i.c.v. cortagine (3 µg/rat) had lesser effects. Cortagine i.p. also increased colonic permeability, activated proximal and distal colonic myenteric neurons and induced visceral hypersensitivity to a 2nd set of colorectal distention (CRD). The CRF antagonist astressin (10 µg/kg, i.p.) abolished i.p. cortagine-induced hyperalgesia while injected i.c.v. had no effect. In mice, cortagine (30 µg/kg, i.p.) stimulated defecation by 7.8-fold, induced 60% incidence of diarrhea and increased VMR to CRD. Stress-like colonic alterations induced by i.p. cortagine in rats and mice that acts peripherally to induce a CRF1 restricted activation of receptors supports a role of peripheral CRF1 signaling as the local arm of the colonic response to stress.
