Modulation of central endocannabinoid system results in gastric mucosal protection in the rat.

Previous findings showed that inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), degrading enzymes of anandamide (2-AEA) and 2-arachidonoylglycerol (2-AG), reduced the nonsteroidal anti-inflammatory drug-induced gastric lesions. The present study aimed to investigate: i./whether central or peripheral mechanism play a major role in the gastroprotective effect of inhibitors of FAAH, MAGL and AEA uptake, ii./which peripheral mechanism(s) may play a role in mucosal protective effect of FAAH, MAGL and uptake inhibitors. METHODS: Gastric mucosal damage was induced by acidified ethanol. Gastric motility was measured in anesthetized rats. Catalepsy and the body temperature were also evaluated. Mucosal calcitonin gene-related peptide (CGRP), somatostatin concentrations and superoxide dismutase (SOD) activity were measured. The compounds were injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.). RESULTS: 1. URB 597, JZL184 (inhibitors of FAAH and MAGL) and AM 404 (inhibitor of AEA uptake) decreased the mucosal lesions significantly given either i.c.v. or i.p. 2. URB 937, the peripherally restricted FAAH inhibitor failed to exert significant action injected i.p. 3. Ethanol-induced decreased levels of mucosal CGRP and somatostatin were reversed by URB 597, JZL 184 and AM 404, the decreased SOD activity was elevated significantly by URB 597 and JZL 184. 4. Neither compounds given i.c.v. influenced gastric motility, elicited catalepsy, or hypothermia. CONCLUSION: Elevation of central endocannabinoid levels by blocking their degradation or uptake via stimulation of mucosal defensive mechanisms resulted in gastroprotective action against ethanol-induced mucosal injury. These findings might suggest that central endocannabinoid system may play a role in gastric mucosal defense and maintenance of mucosal integrity.

Gastric mucosal protection: from the periphery to the central nervous system.

Gastric mucosal integrity can be influenced both by peripheral and central mechanisms. In the periphery several protective factors play a role in gastric mucosal defense. Moreover, receptors located in the gastric mucosa (e.g. toll-like receptors, proteinase-activated receptors, α2-adrenoceptors, opioid receptors) may also be involved in the regulation of gastric mucosal integrity. Activation of peripheral δ-opioid receptors by opioid peptides was shown to induce gastric mucosal defense. In contrast, the gastroprotective action mediated by α2-adrenoceptors (α2B/C-subtypes) is likely to be initiated centrally. Namely, central nervous system (CNS) is also involved in the regulation of gastrointestinal functions; hypothalamus and dorsal vagal complex (DVC) have prominent role in this process. In DVC several receptors have been identified, among others, µ and δ-opioid-, α2-adrenergic-, cannabinoid CB1- and CB2-, angiotensin II AT1-, nociceptin NOP-, neurokinin NK1- and TRH-receptors. Activation of these receptors results in gastric mucosal protection, mainly in a vagal dependent manner. In addition, glutamate (together with GABA and norepinephrine) is involved in synaptic connections between nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV) neurons. AP-7, a selective NMDA receptor antagonist blocked the gastroprotective effect of opioid peptides, indicating that N-Methyl-D-aspartic acid (NMDA) might play a role in centrally induced gastroprotective effect. Moreover, interactions between neuropeptides may have also importance in centrally initiated gastric mucosal protection. Clarification of the role of neuropeptides in gastric mucosal defense may serve as a basis for the development of new strategies to enhance gastric mucosal resistance against injury.