Capsaicin-sensitive afferent neurons are involved in maintaining the integrity of the gastrointestinal 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 micrograms/100 g body wt x 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%).(ABSTRACT TRUNCATED AT 250 WORDS)