urb-597 and Hypothermia

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.. 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.).. 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.. 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.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Benzamides; Benzodioxoles; Calcitonin Gene-Related Peptide; Carbamates; Catalepsy; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Endocannabinoids; Ethanol; Gastric Mucosa; Gastrointestinal Motility; Hypothermia; Male; Piperidines; Rats; Rats, Wistar; Somatostatin; Stomach Diseases; Superoxide Dismutase

The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl-biphenyl-3-yl-cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol. The study further reveals that URB597 specifically acts through FAAH and that cannabinoid-1 (CB(1)) receptor is critical for N-arachidonoyl ethanolamide (AEA) mediated ethanol-reinforced behavior as revealed by lack of URB597 effect in both FAAH and CB(1)-/- mice compared with vehicle-treated -/- mice. The FAAH -/- mice displayed a lower sensitivity to hypothermic and sedative effects to acute ethanol challenge. The FAAH -/- mice also exhibited a reduction in the severity of handling-induced convulsions following withdrawal from chronic ethanol exposure. The CB(1) receptor and proenkephalin gene expressions, and CB(1) receptor and mu-opioid (MO) receptor-mediated G-protein activation were found to be significantly lower in the caudate-putamen, nucleus accumbens core and shell of FAAH -/- than +/+ mice. Interestingly, the MO receptor-stimulated G-protein signaling was greater in the striatum of FAAH -/- than +/+ mice following voluntary ethanol consumption. These findings suggest that an elevation in the AEA content and its action on the limbic CB(1) receptor and MO receptor might contribute to ethanol-reinforced behavior. Treatment with drugs that decrease AEA tone might prove useful in reducing excessive ethanol consumption.

Topics: Alcohol Drinking; Amidohydrolases; Analgesics; Analgesics, Opioid; Animals; Behavior, Animal; Benzamides; Benzoxazines; Carbamates; Central Nervous System Depressants; Choice Behavior; Drug Interactions; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Ethanol; Guanosine 5'-O-(3-Thiotriphosphate); Hypothermia; Mice; Mice, Inbred C57BL; Mice, Knockout; Morpholines; Motor Activity; Naphthalenes; Protein Binding; Protein Precursors; Receptor, Cannabinoid, CB1