We examined whether capsaicin-sensitive sensory neurons might be involved in the increase in the gastric tissue level of prostaglandins, thereby contributing to reduce the water-immersion restraint stress (WIR)-induced gastric mucosal injury in rats. The gastric tissue levels of calcitonin gene-related peptide (CGRP), 6-keto-PGF₁, and PGE₂ were transiently increased 30 min after WIR. These increases were significantly inhibited by subcutaneous injection of capsazepine (CPZ), a vanilloid receptor antagonist, and by functional denervation of capsaicin-sensitive sensory neurons induced by administration of high-dose capsaicin. Administration of capsaicin (p.o.) and CGRP (i.v.) significantly enhanced the WIR-induced increases in the gastric tissue level of prostaglndins 30 min after WIR, while CGRP (8-37), a CGRP receptor antagonist, significantly inhibited them. Pretreatment with L-nitro-arginine-methyl-ester (L-NAME), a non-selective inhibitor of nitric oxide synthase (NOS), and that with indomethacin (IM) inhibited the WIR-induced increases in gastric tissue levels of prostaglandins, while either pretreatment with aminoguanidine (AG), a selective inhibitor of the inducible form of NOS, or that with NS-398, a selective inhibitor of cyclooxygenase (COX)-2, did not affect them. CPZ, the functional denervation of capsaicin-sensitive sensory neurons, and CGRP (8-37) significantly increased gastric MPO activity and exacerbated the WIR-induced gastric mucosal injury in rats subjected to 4 hr-WIR. Administration of capsaicin and CGRP significantly increased the gastric tissue levels of prostaglandins and inhibited both the WIR-induced increases in gastric MPO activity and gastric mucosal injury 8 hr after WIR. These effects induced by capsaicin and CGRP were inhibited by pretreatment with L-NAME and IM, but not by pretreatment with AG and NS-398. These observations strongly suggest that capsaicin-sensitive sensory neurons might release CGRP, thereby increasing the gastric tissue levels of PGI₂ and PGE₂ by activating COX-1 through activation of the constitutive form of NOS in rats subjected to WIR. Such activation of capsaicin-sensitive sensory neurons might contribute to reduce the WIR-induced gastric mucosal injury mainly by inhibiting neutrophil activation.