Cortagine, a CRF1 agonist, induces stresslike alterations of colonic function and visceral hypersensitivity in rodents primarily through peripheral pathways.
Corticotropin-releasing factor (CRF) 1 receptor (CRF(1)) 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 CRF(1) 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 microg/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 microg/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 mug/kg ip) abolished ip cortagine-induced hyperalgesia whereas injected icv it had no effect. In mice, cortagine (30 microg/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 CRF(1) receptors support a role for peripheral CRF(1) signaling as the local arm of the colonic response to stress.
Larauche
Muriel
M
CURE/Digestive Diseases Research Center, Diseases Research Center, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90073, USA. mlarauche@mednet.ucla.edu
Gourcerol
Guillaume
G
Wang
Lixin
L
Pambukchian
Karina
K
Brunnhuber
Stefan
S
Adelson
David W
DW
Rivier
Jean
J
Million
Mulugeta
M
Taché
Yvette
Y
D000818:Animals; D003106:Colon / Q000294:innervation*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000633:toxicity*; D003672:Defecation / Q000187:drug effects; D003967:Diarrhea / Q000139:chemically induced; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009197:Myenteric Plexus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D010446:Peptide Fragments / Q000008:administration & dosage; D010539:Permeability; D010812:Physical Stimulation; D011312:Pressure; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000819:agonists* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000633:toxicity*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D000099052:CRF Receptor, Type 1
D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D018019:Receptors, Corticotropin-Releasing Hormone; D011993:Recombinant Fusion Proteins; C488590:cortagine; C104416:astressin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone