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This Article Full Text Full Text (PDF) All Versions of this Article: 296/2/G302    most recent 90557.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bradesi, S. Articles by Mayer, E. A. Search for Related Content PubMed PubMed Citation Articles by Bradesi, S. Articles by Mayer, E. A.

NEUROREGULATION AND MOTILITY

Involvement of vasopressin 3 receptors in chronic psychological stress-induced visceral hyperalgesia in rats

¹University of California Los Angeles Center for Neurobiology of Stress, Departments of Medicine, Physiology, and Psychiatry, David Geffen School of Medicine at UCLA, Los Angeles, California; ²AstraZeneca Research and Development, Möndal, Sweden

Submitted 18 September 2008 ; accepted in final form 14 November 2008

Visceral hypersensitivity and stress have been implicated in the pathophysiology of functional gastrointestinal disorders. We used a selective vasopressin 3 (V₃) receptor antagonist SSR149415 to investigate the involvement of the vasopressin (AVP)/V₃ signaling system in the development of stress-induced visceral hyperalgesia in rats. Rats were exposed to a daily 1-h session of water avoidance stress (WAS) or sham WAS for 10 consecutive days. The visceromotor response to phasic colorectal distension (CRD, 10–60 mmHg) was assessed before and after stress. Animals were treated daily with SSR149415 (0.3, 1, or 3 mg/kg ip 30 min before each WAS or sham WAS session), with a single dose of SSR149415 (1 mg/kg ip), or the selective corticotropin-releasing factor 1 (CRF₁) antagonist DMP-696 (30 mg/kg po) before CRD at day 11. Effects of a single dose of SSR149415 (10 mg/kg iv) on acute mechanical sensitization during repetitive CRD (12 distensions at 80 mmHg) were also assessed. In vehicle-treated rats, repeated WAS increased the response to CRD, indicating visceral hypersensitivity. Repeated administration of SSR149415 at 1 or 3 mg/kg completely prevented stress-induced visceral hyperalgesia. Similarly, a single dose of DMP-696 or SSR149415 completely blocked hyperalgesic responses during CRD. In contrast, a single dose of SSR149415 did not affect the acute hyperalgesic responses induced by repeated, noxious distension. These data support a major role for V₃ receptors in repeated psychological stress-induced visceral hyperalgesia and suggest that pharmacological manipulation of the AVP/V₃ pathway might represent an attractive alternative to the CRF/CRF₁ pathway for the treatment of chronic stress-related gastrointestinal disorders.

corticotropin-releasing factor; DMP-696; functional gastrointestinal disorders; irritable bowel syndrome; SSR149415