endomorphin-2 and Stomach-Ulcer

Several human and experimental data suggest the particular importance of gastric protective processes in maintaining mucosal integrity. Both peripheral and central mechanisms are involved in this process. In the periphery, pre-epithelial mucus-bicarbonate layer, mucus, phospholipids, trefoil peptides, prostaglandins, heat shock proteins, sensory neuropeptides, nitric oxide, and hydrogen sulfide may mediate mucosal protection. In the central nervous system hypothalamus and dorsal vagal complex (DVC) have particular important role in the regulation of centrally-induced gastroprotection. Stimulation of paraventricular nuclei either aggravates or inhibits the mucosal injury depending on the ulcer model. Vagal nerve also has a dual role, its activation can induce mucosal injury (by high dose of thyrotropin- releasing hormone (TRH), electrical stimulation), however, integrity of vagal nerve is necessary for gastroprotection induced either peripherally (by PGE2, prostacyclin, adaptive cytoprotection), or centrally (e.g. by neuropeptides). The centrally induced gastroprotection is likely to be vagal dependent, though vagal independent pathways have also been shown. Endomorphin-1 and endomorphin-2, selective μ-opioid receptor ligands, proved to be highly potent and effective gastroprotective agents in ethanol ulcer model (0.03-3 pmol intracerebroventricularly). Inhibition of the degradation of endomorphins by diprotin A resulted in gastroprotective effect, indicating the potential role of these endogenous opioids in the regulation of gastric mucosal integrity. Endomorphin-2 injected intracerebroventricularly restored the reduced levels of CGRP and somatostatin in gastric mucosa induced by ethanol. In conclusion, neuropeptides expressed in dorsal vagal complex and hypothalamus may have a regulatory role in maintaining gastric mucosal integrity by stimulating the formation of mucosal protective compounds.

Topics: Animals; Calcitonin Gene-Related Peptide; Central Nervous System; Ethanol; Gastric Mucosa; Humans; Hypothalamus; Neuropeptides; Oligopeptides; Opioid Peptides; Stomach Ulcer

The aim of the present study was to analyze the potential role of substance P (SP) in gastric mucosal defense and to clarify the receptors and mechanisms that may be involved in it. Gastric ulceration was induced by oral administration of acidified ethanol in male Wistar rats. Mucosal levels of calcitonin gene-related peptide (CGRP) and somatostatin were determined by radioimmunoassay. For analysis of gastric motor activity the rubber balloon method was used. We found that central (intracerebroventricular) injection of SP (9.3-74 pmol) dose-dependently inhibited the formation of ethanol-induced ulcers, while intravenously injected SP (0.37-7.4 nmol/kg) had no effect. The mucosal protective effect of SP was inhibited by pretreatment with neurokinin 1-, neurokinin 2-, neurokinin 3- and μ-opioid receptor antagonists, while δ- and κ-opioid receptor antagonists had no effect. Endomorphin-2 antiserum also antagonized the SP-induced mucosal protection. In the gastroprotective dose range SP failed to influence the gastric motor activity. Inhibition of muscarinic cholinergic receptors, or the synthesis of nitric oxide or prostaglandins significantly reduced the effect of SP. In addition, centrally injected SP reversed the ethanol-induced reduction of gastric mucosal CGRP content. It can be concluded, that SP may induce gastric mucosal protection initiated centrally. Its protective effect is likely to be mediated by endomorphin-2, and vagal nerve may convey the centrally initiated protection to the periphery, where both prostaglandins, nitric oxide and CGRP are involved in mediating this effect.

Topics: Alcohols; Animals; Calcitonin Gene-Related Peptide; Disease Models, Animal; Ethanol; Gastric Mucosa; Injections, Intraventricular; Male; Neurotransmitter Agents; Oligopeptides; Radioimmunoassay; Rats; Rats, Wistar; Stomach Ulcer; Substance P

Increasing number of evidence suggest that gastric mucosal protection can be induced also centrally. Several neuropeptides, such as TRH, amylin, adrenomedullin, enkephalin, beta-endorphin, nociceptin, nocistatin, ghrelin or orexin given centrally induce gastroprotection and the dorsal vagal complex and vagal nerve may play prominent role in this centrally initiated effect. Since also cannabinoid receptors are present in the dorsal vagal complex, we aimed to study whether activation of central cannabinoid receptors result in gastric mucosal defense and whether there is an interaction between cannabinoids and endogenous opioids. Gastric mucosal damage was induced by 100% ethanol in rats. The cannabinoids were given intravenously (i.v.) or intracerebroventricularly (i.c.v.), while the antagonists were given i.c.v or intracisternally (i.c.). Gastric lesions were evaluated macroscopically 60 min later. Anandamide, methanandamide and WIN55,212-2 reduced ethanol-induced mucosal lesions after both peripheral (0.28-5.6 micromol/kg, 0.7-5.6 micromol/kg and 0.05-0.2 mumol/kg i.v., respectively) and central (2.9-115 nmol/rat, 0.27-70 nmol/rat and 1.9-38 nmol/rat i.c.v., respectively) administration. The gastroprotective effect of anandamide and methanandamide given i.c.v. or i.v.was reversed by the CB(1) receptor antagonist SR141716A (2.16 nmol i.c.v.). Naloxone (27.5 nmol i.c.v.) also antagonized the effect of i.c.v. or i.v. injected anandamide and WIN55,212-2, but less affected that of methanandamide. The gastroprotective effect of anandamide was diminished also by endomorphin-2 antiserum. In conclusion it was first demonstrated that activation of central CB(1) receptors results in gastroprotective effect. The effect is mediated at least partly by endogenous opioids.

Topics: Analgesics, Opioid; Animals; Anti-Ulcer Agents; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoid Receptor Modulators; Cannabinoids; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Hydrogen-Ion Concentration; Injections, Intraventricular; Male; Narcotic Antagonists; Neuropeptides; Oligopeptides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Severity of Illness Index; Stomach Ulcer

Beta-endorphin, deltorphin II, [D-Ala2, Phe4, Gly5-ol-enkephalin (DAGO) as well as endomorphin-1 and endomorphin-2 injected intracerebroventricularly (i.c.v.) induced gastroprotective action. It has been raised that endogenous opioids may have a central role in maintaining gastric mucosal integrity. Therefore we aimed to study the role of endogenous opioid system in the gastroprotective action induced by activation of alpha 2-adrenoceptors, nociceptin- and cannabinoid-receptors. Our results suggest that the non-selective opioid receptor antagonist naloxone (27 nmol i.c.v.) and the delta-opioid receptor antagonist naltrindole (5 nmol i.c.v.) abolished the mucosal protective effect of alpha 2-adrenoceptor agonists clonidine (470 pmol i.c.v.) and rilmenidine (45 pmol i.c.v.), nociceptin (1 nmol i.c.v.) and the cannabinoid receptor agonist anandamide (110 nmol i.c.v.). Based on our findings it can be raised that opioid system besides its well known regulatory functions might be involved in maintenance of gastric mucosal integrity.

Topics: Animals; Arachidonic Acids; beta-Endorphin; Clonidine; Endocannabinoids; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Ethanol; Excitatory Amino Acids; Gastric Mucosa; Injections, Intraventricular; Male; Naloxone; Naltrexone; Narcotic Antagonists; Neurotransmitter Agents; Nociceptin; Oligopeptides; Opioid Peptides; Oxazoles; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptors, Opioid; Rilmenidine; Stomach Ulcer