Background/Aim: We examined the prophylactic effect of lafutidine, a novel histamine H₂-receptor antagonist [(±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2 butenyl]acetamide], on indomethacin-induced small intestinal ulcers in rats and investigated the relation of this action to capsaicin-sensitive sensory neurons. Methods and Results: Subcutaneously administered indomethacin (10 mg/kg) provoked ulceration in the small intestine, mainly the jejunum and ileum, accompanied by increases in myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities as well as the enterobacterial numbers invading the mucosa. Intestinal ulcerogenic response to indomethacin was prevented by 16,16-dimethyl prostaglandin E₂ (10 μg/kg, p.o.) and capsaicin (10 mg/kg, p.o.) as well as ampicillin (800 mg/kg, p.o.), but not omeprazole (100 mg/kg, p.o.). Likewise, lafutidine (1–10 mg/kg, p.o.), but not cimetidine (100 mg/kg, p.o.), reduced the occurrence of intestinal ulcers in response to indomethacin in a dose-dependent manner, and a significant effect was observed at 3 mg/kg or greater. The protective action of lafutidine as well as capsaicin was almost totally abolished by chemical ablation of capsaicin-sensitive sensory neurons. Both lafutidine and capsaicin significantly suppressed the increases in MPO and iNOS activities as well as enterobacterial numbers in the mucosa. These agents also significantly enhanced mucus secretion in the small intestine. Conclusion: These results suggest that lafutidine protects the small intestine against ulceration via stimulation of capsaicin-sensitive sensory neurons. This action may be attributable to inhibition of enterobacterial invasion in the intestinal mucosa, probably by increasing the mucus secretion.

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These results suggest that lafutidine, but not cimetidine, protects the stomach against NH2Cl, whether occurring endogenously or administered exogenously and that this action may be mediated by capsaicin-sensitive sensory neurons.