Background & Aims: The phenomenon by which the gastric mucosa is protected in response to mild irritants has been called adaptive cytoprotection, a mechanism believed to be related to production of endogenous prostaglandins (PGs). We tested whether PGs generated by mild irritant prevent injury through the release of calcitonin gene-related peptide (CGRP) from the sensory nerves using prostanoid receptor-knockout mice. Methods: The stomach was doubly cannulated and perfused with 1 mol/L NaCl or 50% ethanol. CGRP levels in the perfusate were determined by enzyme immunoassay, and the injured area was estimated at the end of perfusion. Results: Preperfusion with mildly hypertonic saline (1 mol/L NaCl) increased generation of gastric PGE 2 and PGI 2 and reduced ethanol-induced mucosal damage. Exposure of ethanol after 1 mol/L NaCI increased intragastric CGRP levels from 166 ± 27 to 713 ± 55 pg/2 min (n = 4, P < 0.05), and the protective action of 1 mol/L NaCl was inhibited by indomethacin treatment. CGRP antagonist blocked 1 mol/L NaClinduced protective effect. Intragastric perfusion of 50% ethanol after administration of PGI 2 , but not of PGE 2 , increased CGRP levels. Application of 1 mol/L NaCl to IP receptor-knockout mice (IP −/− ) did not elicit the protective effects seen in the wild-type on ethanol-induced gastric mucosal lesions. Protective effect of 1 mol/L NaCl was observed in EP3 receptor-knockout mice (EP3 −/− ). CGRP level during ethanol perfusion was not increased in IP −/− but was increased in EP3 −/− and wild-type counterparts after preperfusion of 1 mol/L NaCl. Conclusions: These results indicate that the endogenous PGI 2 generated by 1 mol/L NaCl may have a protective role in gastric mucosal injury through enhancement of CGRP release from gastric mucosa. This mechanism may explain the adaptive cytoprotection observed after treatment with mild irritants.