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Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs

Molecular Psychiatry volume 7, pages 474–483 (2002)Cite this article

Abstract

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 CRH-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.

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Acknowledgements

We thank Dr Rita J Valentino for her thoughtful discussion and Mr Keith Zachman for his help in conducting the animal experiments.

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Authors and Affiliations

  1. Clinical Neuroendocrinology Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    K E Gabry, E Sternberg, A B Negrao, E L Webster & P W Gold

  2. Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    G P Chrousos

  3. Laboratory of Medicinal Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA

    K C Rice

  4. Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    R M Mostafa

  5. Pennington Biomedical Research Laboratories, Louisiana State University, Baton Rouge, LA, USA

    S M McCann

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  1. K E Gabry
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Correspondence to K E Gabry.

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Gabry, K., Chrousos, G., Rice, K. et al. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Mol Psychiatry 7, 474–483 (2002). https://doi.org/10.1038/sj.mp.4001031

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