Inhibition of Monoacylglycerol Lipase Attenuates Nonsteroidal Anti-Inflammatory Drug-Induced Gastric Hemorrhages in Mice

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used analgesics, but can cause gastric and esophageal hemorrhages, erosion, and ulceration. The endogenous cannabinoid (endocannabinoid; eCB) system possesses several potential targets to reduce gastric inflammatory states, including cannabinoid receptor type 1 (CB 1 ), cannabinoid receptor type 2 (CB 2 ), and enzymes that regulate the eCB ligands 2-arachidonoylglycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide; AEA). In the presented study, we tested whether 4-nitrophenyl, a selective inhibitor of the primary catabolic enzyme of 2-AG, monoacylglycerol lipase (MAGL), would protect against NSAID-induced gastric damage. Food-deprived mice administered the nonselective cyclooxygenase inhibitor diclofenac sodium displayed gastric hemorrhages and increases in proinflammatory cytokines. JZL184, the proton pump inhibitor omeprazole (positive control), or the primary constituent of marijuana, ⌬ 9 -tetrahydrocannabinol (THC), significantly prevented diclofenac-induced gastric hemorrhages. JZL184 also increased stomach levels of 2-AG, but had no effect on AEA, arachidonic acid, or the prostaglandins E 2 and D 2 . MAGL inhibition fully blocked diclofenac-induced increases in gastric levels of proinflammatory cytokines interleukin (IL)-1␤, IL-6, tumor necrosis factor ␣, and granulocyte colony-stimulating factor, as well as IL-10. Pharmacological inhibition or genetic deletion of CB 1 or CB 2 revealed that the gastroprotective effects of JZL184 and THC were mediated via CB 1 . The antihemorrhagic effects of JZL184 persisted with repeated administration, indicating a lack of tolerance. These data indicate that increasing 2-AG protects against gastric damage induced by NSAIDs, and its primary catabolic enzyme MAGL offers a promising target for the development of analgesic therapeutics possessing gastroprotective properties.

Repeated Low-Dose Administration of the Monoacylglycerol Lipase Inhibitor JZL184 Retains Cannabinoid Receptor Type 1–Mediated Antinociceptive and Gastroprotective Effects

“…JZL184 has anti-inflammatory effects in a model of gastric hemorrhagic lesions caused by the nonsteroidal antiinflammatory drug (NSAID) diclofenac ( 2-(2,6-dichloranilino) phenylacetic acid) sodium (Kinsey et al, 2011b). However, the gastroprotective effects of JZL184 persisted after repeated administration.…”

“…Third, we tested the gastroprotective and antiallodynic effects of low-dose and high-dose administration of JZL184 following repeated administration in two whole animal function assays: the nonsteroidal anti-inflammatory drug (NSAID)-induced gastric hemorrhage model and the chronic constriction injury (CCI) neuropathic pain model. Whereas previous research has found that the antiallodynic actions of high-dose JZL184 undergo tolerance following repeated administration in the CCI model, and low-dose JZL184 given acutely or repeatedly blocks the gastric inflammatory effects of the NSAID diclofenac sodium in mice (Kinsey et al, 2011b), the consequences of other doses in these assays have yet to be assessed. Thus, JZL184 (4-40 mg/kg) was administered acutely or repeatedly, followed by gastric hemorrhage induction by the nonsteroidal antiinflammatory drug diclofenac.…”

“…However, the gastroprotective effects of JZL184 persisted after repeated administration. A key distinction between these two reports is that 4 mg/kg JZL184 was used in the gastric hemorrhage study (Kinsey et al, 2011b), but 40 mg/kg JZL184 was used in the investigation by Schlosburg and colleagues (2010). Similarly, the antinociceptive effects of low-dose JZL184 persisted after repeated administration in the acetic acid-induced abdominal stretching model of visceral pain (Busquets-Garcia et al, 2011) and carrageenan-induced inflammatory pain (Ghosh et al, 2012).…”

“…Similarly, the selective MAGL inhibitor 4-nitrophenyl 4-(dibenzo [d] [1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) attenuates nociception in neuropathic (Kinsey et al, 2009) and inflammatory (Ghosh et al, 2012) pain models. JZL184 also decreases gastric hemorrhaging (Kinsey et al, 2011b) and produces anxiolytic-like behavior in mice (Kinsey et al, 2011c) and rats (Sciolino et al, 2011).…”

Elevating endocannabinoid levels: pharmacological strategies and potential therapeutic applications

“…It is noteworthy, therefore, that carprofen, a compound that has been reported to produce fewer ulcerogenic side effects in human subjects than other NSAID, has been found to be a multi-inhibitor of COX-1, COX-2 and FAAH (83) . It is noteworthy, too, first that the peripherally restricted FAAH inhibitor, URB937, has been found in mice both to interact synergistically with the NSAID, indomethacin, to reduce signs of inflammatory and neuropathic pain and to lower the number and severity of indomethacin-induced gastric lesions (34) , and second, that the MAG lipase inhibitor, JZL184, has also been found to protect against NSAID-induced gastric damage in mice (62) . Other potential adjunctive therapeutic strategies include the combined administration of a FAAH inhibitor, with a COX-2 inhibitor and a low dose of a glucocorticoid for rheumatoid arthritis (84) , with palmitoylethanoamide for the treatment of melanoma (85) , with morphine for relieving visceral pain (23) , and with an inhibitor of the metabolism of endogenous opioids (enkephalins) for the alleviation of inflammatory and neuropathic pain (86) .…”