When exposed to prolonged stress, rats develop gastric ulceration, enhanced colon motility
with depletion of its mucin content and signs of physiological and behavioral arousal. In this
model, we tested whether antidepressants (fluoxetine and bupropion), anxiolytics (diazepam
and buspirone) or the novel nonpeptide corticotropin-releasing hormone (CRH) type-1 receptor
(CRH-R1) antagonist, antalarmin, modify these responses. Fluoxetine, bupropion,
diazepam and antalarmin all suppressed stress-induced gastric ulceration in male Sprague—
Dawley rats exposed to four hours of plain immobilization. Antalarmin produced the most
pronounced anti-ulcer effect and additionally suppressed the stress-induced colonic hypermotility,
mucin depletion, autonomic hyperarousal and struggling behavior. Intraperitoneal
CRH administration reproduced the intestinal but not the gastric responses to stress while
vagotomy antagonized the stress-induced gastric ulceration but not the intestinal responses.
We conclude that brain CRH-R1 and vagal pathways are essential for gastric ulceration to
occur in response to stress and that peripheral CR11-R1 mediates colonic hypermotility and
mucin depletion in this model. Nonpeptide CRH-R1 antagonists may therefore be prophylactic
against stress ulcer in the critically ill and therapeutic for other pathogenetically related gastrointestinal
disorders such as peptic ulcer disease and irritable bowel syndrome. |
