We examined the effect of lafutidine, a novel histamine H₂-receptor antagonist, on acid reflux esophagitis in rats in relation to capsaicin-sensitive afferent neurons. The esophagitis was induced in rats by ligating both the pylorus and forestomach for 4 h. Lafutidine (1 – 30 mg/kg) and cimetidine (100 mg/kg) were administered either intragastrically or intraduodenally, while capsaicin (1 – 30 mg/kg) was administered intragastrically after the dual ligation. Intragastrical administered lafutidine at >3 mg/kg significantly prevented the hemorrhagic esophageal damage induced by the dual ligation, and this effect was mimicked by neither capsaicin nor cimetidine given intragastrically, but totally abolished by sensory deafferentation. In contrast, lafutidine and cimetidine given intraduodenally were both protective against the esophageal damage in a sensory deafferentation-resistant manner. The acid secretion in pylorus-ligated stomachs was significantly inhibited by these agents given intraduodenally, but not intragastrically. Vanilloid receptor subtype 1 (VR1) was expressed abundantly in the stomach, but very weakly expressed in the esophagus as assessed by Western blotting. These results suggest that lafutidine is effective against the esophageal lesions induced by acid reflux through inhibition of acid secretion and capsaicin-sensitive afferent neurons. The latter mechanism, not shared by cimetidine, may be due to the interaction of lafutidine with unidentified sites on sensory neurons other than VR1.