Abstract
Capsaicin-sensitive afferent neurons are involved in maintaining the integrity of the gastro-intestinal mucosa. These neurons are closely apposed to mast cells and could, therefore, lead to their activation. In the present study, the role of capsaicin-sensitive neurons in the pathogenesis of experimental colitis and the possible involvement of mast cells and nitric oxide were evaluated. Rats were treated with capsaicin subcutaneously, 20, 30, and 50 mg/kg, on three consecutive days, a regimen shown to ablate primary afferent neurons. Colitis was induced two weeks later by flushing 2 ml 5% acetic acid into the proximal colon. Control rats received saline, acetic acid, or capsaicin alone. Another group of rats received ketotifen (100 µg/100 g body wt × 2/day) intragastrically 48 hr prior to damage induction and thereafter. Rats were sacrificed 24 hr after damage induction, the colon isolated, damage assessed, explants were organ-cultured for 24 hr for determination of nitric oxide generation, and mucosa extracted for determination of leukotriene B4 generation and nitric oxide synthase activity. Significant increases in colonic weight, nitric oxide synthase activity, and nitric oxide and leukotriene B4 generation accompanied the near tripling of acetic acid-induced damage in capsaicin-pretreated rats. Ketotifen pretreatment significantly decreased the macroscopic damage and the increase in colonic weight. The protection provided by ketotifen was accompanied by a significant decrease in leukotriene B4 generation and nitric oxide synthase activity (80%). The correlation between the extent of colonic damage, nitric oxide synthase activity, and nitric oxide generation in acetic acid-induced colitis in capsaicin-pretreated rats suggests possible involvement of nitric oxide in its pathogenesis. The protective effect of ketotifen in capsaicin-pretreated rats indicates that mast cell activation is not prevented by ablation of afferent neurons.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Eliakim R, Rachmilewitz D: Potential mediators in inflammatory bowel disease. Gastroenterol Int 5:48–56, 1992
Mannaioni PF, Masini E, Pistelli A, Salvemini D, Vane JR: Mast cells as a source of superoxide anions and nitric oxide-like factor: Relevance to histamine release. Int J Tissue Reac 13:271–278, 1991
Kanwar S, Wallace JL, Befus D, Kubes P: Nitric oxide modulates mucosal barrier function: A potential role of mast cells. Gastroenterology 105:A249, 1993
Oates PJ, Hakkinen JP: Studies on the mechanism of ethanol induced gastric damage in rats. Gastroenterology 94:10–21, 1988
Rioux KP, Wallace JL: Activation of mucosal mast cells augments gastric mucosal injury. Gastroenterology 105:A401, 1993
Stead RH, Tomioka M, Riddell RH, Bienenstock J: Substance P and/or calcitonin gene related peptide are present in subepithelial enteric nerves apposed to intestinal mucosal mast cells.In: Inflammatory Bowel Disease: Current Status and Future Approach. RP MacDermott (ed). Amsterdam, Elsevier Scientific Publications, 1988, pp 43–48
Whittle BJR, Lopez-Belmonte J: Gastric mucosal damage and protection: Involvement of novel endothelium-derived mediators. In: The Stomach, Physiology, Pathophysiology and Treatment. W Domschke, SJ Konturek (eds). Berlin, Springer-Verlag, 1993, pp 68–82
Lambrecht N, Butchert H, Responde KM, Muller K-M, Peskar BM: Role of calcitonin gene-related peptide and nitric oxide in the gastroprotective effect of capsaicin. Gastroenterology 104:1371–1380, 1993
Wang L, Stanisz AM, Perdue MH: Activation of mast cells by substance P in the regulation of ion secretion in mouse small intestine. Gastroenterology 104:A156, 1993
Wallace JL, McKnight GW, Befus D: Capsaicin induced hyperemia in the stomach: Possible contribution of mast cells. Am J Physiol 263:G209-G214, 1992
Crowe SE, Perdue MH: Gastrointestinal food hypersensitivity: Basic mechanisms of pathophysiology. Gastroenterology 103:1075–1095, 1992
Eliakim R, Karmeli F, Okon E, Rachmilewitz D: Ketotifen effectively prevents mucosal damage in experimental colitis. Gut 33:1498–1503, 1992
Pothoulakis C, Karmeli F, Kelly CP, Eliakim R, Joshi MA, O'Keane CJ, Castaglivolo I, LaMont JT, Rachmilewitz D: Ketotifen inhibits clostridium difficile toxin A-induced enteritis in rat ileum. Gastroenterology 105:701–707, 1993
Szolcanyi J, Bartho L: Impaired defense mechanism to peptic ulcer in the capsaicin desensitized rat. In: Advanced Physiological Sciences, Vol 15, Gastrointestinal Defense Mechanisms. GY Mozsic, O Hanninen, T Javor (eds). Oxford, Pergamon Press, 1981, pp 39–51
Martling CR: Sensory nerves containing tachykinins and cGRP in the lower airways. Acta Physiol Scand 563(suppl):1–57, 1987
Rachmilewitz D, Stamler JS, Karmeli F, Mullins ME, Singel DJ, Loscalzo J, Xavier RJ, Podolsky DK: Peroxynitrite-induced rat colitis—a new model of colonic inflammation. Gastroenterology 105:1681–1688, 1993
Bush PA, Gonzalez NE, Griscavage JM, Ignarro LJ: Nitric oxide synthase from cerebellum catalyzes the formation of equimolar quantities of nitric oxide and citrulline froml-arginine. Biochem Biophys Res Commun 185:960–966, 1992
Sharkey KA, Williams RG, Dockray GJ: Sensory substance P innervation of the stomach and pancreas. Demonstration of capsaicin-sensitive sensory neurons in the rat by combined immunohistochemistry and retrograde tracing. Gastroenterology 87:914–921, 1984
Leung FN: Role of capsaicin-sensitive afferent nerves in mucosal injury and injury-induced hyperemia in rat colon. Am J Physiol 262:G332–337, 1992
Domek MJ, Blackman E, Vidrich A, Kao J, Baker M, Leung FW: Capsaicin pretreatment increases severity of dextran sulfate sodium (DSS)-induced colonic damage in rats. Gastroenterology 105:A615, 1993
Reinshagen M, Patel A, Sottili M, Procaccino F, French S, Eysslein VE: Effect of sensory neurons in chronic colitis. Gastroenterology 105:A173, 1993
Barret KE: Involvement of histamine in a rat model of inflammatory bowel disease. Gastroenterology 98:A653, 1990
Rachmilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z, Loscalzo J, Podolsky DK: Enhanced colonic NO generation and stimulated NO synthase activity in experimental colitis and in active inflammatory bowel disease. Gastroenterology 105:A236, 1993
Boughton-Smith NK, Evans SM, Cole AT, Hawkey CJ, Whittle BJR, Moncada S: Induction of nitric oxide synthase in inflamed colon from ulcerative colitis patients. Gastroenterology 105:A236, 1993
Mourelle M, Videla S, Vilaseca J, Guarner F, Malagelada JR: Induction of nitric oxide synthase in the course of toxic megacolon in a rat model of colitis. Gastroenterology 105:A237, 1993
Miller HJS, Sadowska-Krowicka A, Chotinaruemol S, Kakkis JL, Clark DA: Amelioration of chronic ileitis by nitric oxide synthase inhibition. J Pharmacol Exp Ther 264:11–16, 1993
Stenson WF, Lauristen K, Laursen LS, Rask-Madsen J, Jacobsen O, Naesdal J, Cort D, Goebell H, Peskar B, Hanaver S, Swanson L, Dube L, Rubin P: A clinical trial of Zileuton, a specific inhibitor of 5-lipoxygenase in ulcerative colitis. Gastroenterology 100:A253, 1991.
Sharon P, Stenson WF: Enhanced synthesis of leukotriene B4 by colonic mucosa in inflammatory bowel disease. Gastroenterology 86:453–460, 1984
Wallace JL, MacNaughton WK, Morris GP, Beck PL: Inhibition of leukotriene synthesis markedly accelerated healing in a rat model of inflammatory bowel disease. Gastroenterology 96:29–36, 1989
Fretland DJ, Levin S, Tsai BS, Djuric SW, Widomski DL, Zemaitis JM, Shone RL, Bauer RF: The effect of leukotriene B4 receptor antagonist, SC-41930, on acetic acid induced colonic inflammation. Agents Actions 27:395–397, 1989
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Eliakim, R., Karmeli, F., Okon, E. et al. Ketotifen ameliorates capsaicin-augmented acetic acid-induced colitis. Digest Dis Sci 40, 503–509 (1995). https://doi.org/10.1007/BF02064357
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02064357