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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.

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, d-Lys(3)-GHRP-6; blockade of cyclooxygenase (COX)-1 (indomethacin, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]) and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE(2) generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with d-Lys(3)-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E(2). The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.

This review was designed to show the role of expression of cyclooxygenase (COX)-1 and COX-2 in the cancerogenesis of esophagus, stomach and colon. Unlike COX-1, which is expressed in the normal esophago-gastro-colonic mucosa, COX-2 was found to be expressed mainly in the pre-cancer changes in the mucosa including Barrett's esophagus, Helicobacter pylori (H. pylori)-induced gastritis and inflammatory changes in colonic mucosa. In Barrett's esophagus, prostaglandins (PGs) derived from upregulated COX-2 contribute to the progression of low-grade to high-grade dysplasia and finally to cancer. In chronic gastritis induced by chronic H. pylori infection, overexpression of COX-2 is probably induced by inflammatory cytokines, growth factors, especially gastrin and reactive oxygen species leading to mutagenesis and subsequent metaplasia, dysplasia and cancer formation. The imbalance between cell proliferation and apoptosis caused mainly by products of COX-2 leads to cancerogenesis. Similarly, in colorectal cancer the overexpression of COX-2, possibly induced by the action of growth promoting factors including progastrin and gastrin and overexpression of survivin contribute to the colorectal cancerogenesis that could be, at least in part, amended by the treatment with specific COX-2 inhibitors. We conclude that: 1) COX-2-derived PGs play a key role in the tumorigenesis in the gastrointestinal tract; 2) The tumor-promoting effect of PGs may be attributed to their ability to stimulate cell proliferation and migration, to inhibit the apoptosis and to increase angiogenesis and invasiveness; 3) In accordance to the proposed major role of COX-2 in cancerogenesis, selective COX-2 inhibitors have been shown in numerous studies to exhibit strong chemopreventive effect on the development of gastrointestinal cancers.