BACKGROUND Accumulating evidence indicates that orexin-A in the brain stimulates vagal flow projecting to the stomach. Since the vagal system plays an important role in gastric mucosal integrity, we hypothesized that orexin-A in the brain might have a gastroprotective action. METHODS We examined the effect of centrally administered orexin-A on the development of gastric mucosal damage evoked by ethanol and its possible mechanism of action in rats. RESULTS Intracisternal but not intraperitoneal injection of orexin-A significantly inhibited the severity of gastric mucosal damage by 70% ethanol in a dose-dependent manner, suggesting that orexin-A acts in the brain to prevent ethanol-induced gastric mucosal damage. The antiulcer action was observed in rats administered with orexin-A centrally but not orexin-B, indicating that the action is mediated through orexin 1 receptors. The gastroprotective action of centrally administered orexin-A was blocked by pretreatment with atropine, Nomega-nitro-L-arginine methylester, or indomethacin. CONCLUSIONS These results suggest that orexin-A acts on orexin 1 receptors in the brain to exert a gastroprotective action against ethanol. The vagal muscarinic system, nitric oxide, and prostaglandins may mediate the cytoprotective action of centrally administered orexin-A.