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

Abstract

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.

• Authors: Muriel Larauche, Guillaume Gourcerol, Lixin Wang, Karina Pambukchian, Stefan Brunnhuber, David W Adelson, Jean Rivier, Mulugeta Million, Yvette Taché
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 297 Issue 1 Pg. G215-27 (Jul 2009) ISSN: 1522-1547 [Electronic] United States
• PMID: 19407218 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Peptide Fragments
• Proto-Oncogene Proteins c-fos
• Receptors, Corticotropin-Releasing Hormone
• Recombinant Fusion Proteins
• cortagine
• astressin
• CRF receptor type 1
• Corticotropin-Releasing Hormone

Topics

• Animals
• Colon (innervation)
• Corticotropin-Releasing Hormone (administration & dosage, toxicity)
• Defecation (drug effects)
• Diarrhea (chemically induced)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gastrointestinal Motility (drug effects)
• Gastrointestinal Transit (drug effects)
• Hyperalgesia (chemically induced, metabolism, physiopathology, prevention & control)
• Injections, Intraperitoneal
• Injections, Intraventricular
• Male
• Mice
• Mice, Inbred C57BL
• Myenteric Plexus (drug effects, metabolism, physiopathology)
• Neural Pathways (drug effects, metabolism, physiopathology)
• Pain Measurement
• Peptide Fragments (administration & dosage)
• Permeability
• Physical Stimulation
• Pressure
• Proto-Oncogene Proteins c-fos (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Corticotropin-Releasing Hormone (agonists, metabolism)
• Recombinant Fusion Proteins (administration & dosage, toxicity)
• Stress, Psychological (metabolism, physiopathology)