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.