Brain orexin improves intestinal barrier function via the vagal cholinergic pathway.

Orexins are neuropeptides that are implicated in a number of functions. With regard to the gastrointestinal functions, orexin acts centrally to regulate gastric secretion, gastrointestinal motility and visceral sensation. Little is however known about a role of central orexin in the control of intestinal barrier function. The present study was performed to clarify whether brain orexin plays a role in the control of intestinal permeability. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternally administered orexin-A but not orexin-B dose-dependently blocked the increased intestinal permeability by lipopolysaccharide (LPS) or corticotropin-releasing factor while intraperitoneally injected orexin-A failed to block it. Atropine or vagotomy abolished the action by central orexin-A. Intravenous injection of 2-deoxy-D-glucose (2-DG), a central vagal stimulant, significantly blocked the LPS-induced increase in intestinal permeability and atropine prevented the action of 2-DG. Intracisternal injection of SB-334687, a selective orexin 1 receptor antagonist, significantly blocked the action of 2-DG-induced improvement of intestinal hyperpermeability. These results suggest that exogenously administered or endogenously released orexin acts centrally to improve the intestinal hyperpermeability by LPS via the vagal cholinergic pathway. The findings also suggest for the first time that the brain could control intestinal permeability. The neuronal rapid protective advantage to the host by improving the intestinal barrier function by the neuropeptide may help us understand the brain-gut interaction in stress sensitive gastrointestinal disorders like irritable bowel syndrome associated with the altered intestinal permeability.