Corticotropin-releasing factor type 1 receptors mediate the visceral hyperalgesia induced by repeated psychological stress in rats.
Visceral hypersensitivity has been implicated as an important pathophysiological mechanism in functional gastrointestinal disorders. In this study, we investigated whether the sustained visceral hyperalgesia induced by repeated psychological stress in rats involves the activation of CRF(1) signaling system using two different antagonists. Male Wistar rats were exposed to 10 consecutive days of water avoidance stress (WAS) or sham stress for 1 h/day, and the visceromotor response to phasic colorectal distension (CRD) was assessed before and after the stress period. Animals were injected subcutaneously with the brain penetrant CRF(1) antagonist, CP-154,526, acutely (30 min before the final CRD) or chronically (via osmotic minipump implanted subcutaneously, during stress) or with the peripherally restricted, nonselective CRF(1) and CRF(2) antagonist, astressin, chronically (15 min before each stress session). Repeated WAS induced visceral hypersensitivity to CRD at 40 and 60 mmHg. CP-154,526 injected acutely significantly reduced stress-induced visceral hyperalgesia at 40 mmHg but not at 60 mmHg. Chronic subcutaneous delivery of astressin reduced the stress-induced visceral hyperalgesia to baseline at all distension pressures. Interestingly, chronically administered CP-154,526 eliminated hyperalgesia and produced responses below baseline at 40 mmHg and 60 mmHg, indicating a hypoalgesic effect of the compound. These data support a major role for CRF(1) in both the development and maintenance of visceral hyperalgesia induced by repeated stress and indicate a possible role of peripheral CRF receptors in such mechanisms.
Larauche
Muriel
M
Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.
Bradesi
Sylvie
S
Million
Mulugeta
M
McLean
Peter
P
Taché
Yvette
Y
Mayer
Emeran A
EA
McRoberts
James A
JA
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D002908:Chronic Disease; D003106:Colon / Q000294:innervation*; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage / Q000378:metabolism; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control / Q000523:psychology; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism; D011312:Pressure; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012007:Rectum / Q000294:innervation*; D013315:Stress, Psychological / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D000099052:CRF Receptor, Type 1
C101628:CP 154526; C101531:CRF receptor type 2; D010446:Peptide Fragments; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; C104416:astressin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone