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HORMONES AND SIGNALING

Cortagine, a CRF₁ agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways

¹CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles and ²Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California; and ³Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, California

Submitted 25 February 2009 ; accepted in final form 28 April 2009

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 (ip) injection of cortagine, a newly developed selective CRF₁ peptide agonist. Colonic motor function and visceral motor response (VMR) were monitored by using a modified miniaturized pressure transducer catheter in adult conscious male Sprague-Dawley rats and C57Bl/6 mice. Colonic permeability was monitored by the Evans blue method and myenteric neurons activation by Fos immunohistochemistry. Compared with vehicle, cortagine (10 µg/kg ip) 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, and induced a 7.1-fold increase in defecation and watery diarrhea in 50% of rats during the first hour postinjection whereas intracerebroventricular (icv) cortagine (3 µg/rat) had lesser effects. Intraperitoneal (ip) cortagine also increased colonic permeability, activated proximal and distal colonic myenteric neurons, and induced visceral hypersensitivity to a second set of phasic colorectal distention (CRD). The CRF antagonist astressin (10 µg/kg ip) abolished ip cortagine-induced hyperalgesia whereas injected icv it had no effect. In mice, cortagine (30 µg/kg ip) stimulated defecation by 7.8-fold, induced 60% incidence of diarrhea, and increased VMR to CRD. Stresslike colonic alterations induced by ip cortagine in rats and mice through restricted activation of peripheral CRF₁ receptors support a role for peripheral CRF₁ signaling as the local arm of the colonic response to stress.

CRF₁ agonist; colonic motility; visceral pain; rat; mice; colonic permeability; astressin; CP-154,526