Treatment of newborn rats with capsaicin (0.16 mmol/kg) is known to cause a permanent degeneration of certain, primarily unmyelinated, afferent neurons. In this study, experimentally induced gastric ulceration was investigated in adult rats treated with capsaicin as neonates. It was found that in capsaicin-treated animals the formation of gastric mucosal lesions in response to indomethacin, ethanol, or cysteamine was significantly enhanced as compared with vehicle-treated controls. The duodenal ulceration caused by cysteamine was not altered after capsaicin treatment. In further experiments the possible pathways involved in the effect of capsaicin treatment on gastric mucosal protection were explored. It was found that the capacity of gastric tissue to release prostaglandins E2 and I2 was unchanged after capsaicin treatment. Atropine, hexamethonium, cimetidine, or terbutaline all reduced gastric ulceration in response to indomethacin in both solvent- and capsaicin-treated rats but did not counteract the enhancement of the ulcerogenic effect of indomethacin in capsaicin-treated rats. Guanethidine enhanced the ulcerogenic effect of indomethacin in solvent-treated but not in capsaicin-treated animals. Ethanol-induced formation of gastric lesions remained unaltered by guanethidine in both solvent- and capsaicin-treated rats. These results indicate that capsaicin-sensitive afferent neurons are involved in gastric mucosal protection against ulcerogenic factors. The data further suggest that this type of gastric defense is primarily due to a local mechanism initiated by sensory nerve endings in the gastric mucosa.