We investigated the role of capsaicin-sensitive sensory neurons in regulation of gastroduodenal HCO3- secretion in anesthetized rats. The stomach (under acid inhibition by omeprazole 60 mg/kg i.p.) or the duodenum was perfused with saline (pH 4.5) and HCO3- output was determined by pH change in the perfusate. Both the duodenum and stomach responded to prostaglandin E2 (PGE2; 300 μg/kg i.v.) or luminal acid by a significant increase in pH and HCO3- output. These tissues also responded to luminal application of capsaicin (0.3–6 mg/ml for 30 min), resulting in a significant increase of pH and HCO3- output in a concentration-related manner. The HCO3- stimulatory action of capsaicin was markedly attenuated by functional ablation of capsaicin-sensitive sensory neurons, significantly mitigated by indomethacin, and exhibited tachyphylaxis after repeated application at a high concentration. The acid-induced pH and HCO3- responses were also significantly mitigated by sensory deafferentation and by indomethacin, whereas those induced by PGE2 remained unaffected. In addition, defunctionalization of these sensory nerves resulted in macroscopically visible damage in the duodenum when acid secretion was concomitantly stimulated by histamine. We conclude that capsaicin-sensitive sensory neurons may be involved in the regulatory mechanism of gastroduodenal HCO3-secretion and contribute to protection of the mucosa against acid. Endogenous PGs may be involved in the HCO3- stimulatory action mediated by capsaicin-sensitive sensory neurons.