Gastroprotective action of orexin-A against stress-induced gastric damage is mediated by endogenous prostaglandins, sensory afferent neuropeptides and nitric oxide.
Orexin-A, identified in the neurons and endocrine cells in the gut, has been implicated in control of food intake and sleep behavior but little is known about its influence on gastric secretion and mucosal integrity. The effects of orexin-A on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) or 75% ethanol were determined. Orexin-A (5-80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by WRS and this was accompanied by the significant rise in plasma orexin-A, CGRP and gastrin levels, the gastric mucosal blood flow (GBF), luminal NO concentration and an increase in mRNA for CGRP and overexpression of COX-2 protein and the generation of PGE(2) in the gastric mucosa. Orexin-A-induced protection was abolished by selective OX-1 receptor antagonist, vagotomy and attenuated by suppression of COX-1 and COX-2, deactivation of afferent nerves with neurotoxic dose of capsaicin, pretreatment with CCK(2)/gastrin antagonist, CGRP(8-37) or capsazepine and by inhibition of NOS with L-NNA. This study shows for the first time that orexin-A exerts a potent protective action on the stomach of rats exposed to non-topical ulcerogens such as WRS or topical noxious agents such as ethanol and these effects depend upon hyperemia mediated by COX-PG and NOS-NO systems, activation of vagal nerves and sensory neuropeptides such as CGRP released from sensory nerves probably triggered by an increase in gastric acid secretion induced by this peptide.
Brzozowski
Tomasz
T
Department of Physiology, Jagiellonian University Medical College, Cracow, Poland.
Konturek
Peter C
PC
Sliwowski
Zbigniew
Z
Drozdowicz
Danuta
D
Burnat
Grzegorz
G
Pajdo
Robert
R
Pawlik
Michal
M
Bielanski
Wladyslaw
W
Kato
Ikuo
I
Kuwahara
Atsuzakau
A
Konturek
Stanislaw J
SJ
Pawlik
Wieslaw W
WW
D000818:Animals; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005755:Gastrins / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D008297:Male; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D064446:Orexin Receptors; D000068797:Orexins; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013272:Stomach Diseases / Q000378:metabolism / Q000517:prevention & control*; D013312:Stress, Physiological / Q000503:physiopathology*
D005755:Gastrins; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D011453:Prostaglandins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D009569:Nitric Oxide; D051546:Cyclooxygenase 2; D015740:Calcitonin Gene-Related Peptide