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1 Department of Medicine, Center for Neurovisceral Sciences & Women's Health, Los Angeles, California, United States; David Geffen School of Medicine at UCLA, VAGLAHS, CURE: Digestive Diseases Research Center, Los Angeles, California, United States
2 David Geffen School of Medicine at UCLA, VAGLAHS, CURE: Digestive Diseases Research Center, Los Angeles, California, United States
3 Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D Ltd, Harlow, United Kingdom
4 Department of Medicine, Center for Neurovisceral Sciences & Women's Health, Los Angeles, California, United States; Physiology, Los Angeles, California, United States; Psychiatry and Biobehavioral Sciences and Brain Research Institute, Los Angeles, California, United States; David Geffen School of Medicine at UCLA, VAGLAHS, CURE: Digestive Diseases Research Center, Los Angeles, California, United States
* To whom correspondence should be addressed. E-mail: mcrobert{at}ucla.edu.
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 CRF1 signaling system using two different antagonists. Male Wistar rats were exposed to 10 consecutive days of water avoidance stress (WAS) or sham stress for one hour/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 CRF1 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, non-selective CRF1 and CRF2 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 CRF1 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.
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