Accumulating evidence have indicated that orexin-A in the brain stimulates vagal flow projecting to the stomach. Since the vagal system palys an important role in gastric mucosal integrity, we examined in the present study the effect of central orexin-A on the development of gastric mucosal damage evoked by ethanol in rats. 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 anti-ulcer action was observed in rats received with central administration of orexin-A but not orexin-B, indicating that the action is mediated through orexin 1 receptors. The gastroprotective action of central orexin-A was blocked by pretreatment with atropine, N^w-nitro-L-arginine methylester or indomethacin, respectively All these results suggest that orexin-A acts in orexin 1 receptors in the brain to exert a gastroprotective action against ethanol. Vagal muscarinic system, nitric oxide and prostaglandins may mediate the cytoprotective action by central orexin-A.
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