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Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice
Author(s) -
Crowe Molly S,
Leishman Emma,
Banks Matthew L,
Gujjar Ramesh,
Mahadevan Anu,
Bradshaw Heather B,
Kinsey Steven G
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13012
Subject(s) - pharmacology , monoacylglycerol lipase , neuropathic pain , diclofenac , allodynia , endocannabinoid system , analgesic , rimonabant , medicine , cannabinoid , cannabinoid receptor , hyperalgesia , antagonist , chemistry , receptor , nociception
Background and Purpose Neuropathic pain is commonly treated with GABA analogues, steroids or non‐steroidal anti‐inflammatory drugs ( NSAIDs ). NSAIDs inhibit one or more COX isozymes but chronic COX inhibition paradoxically increases gastrointestinal inflammation and risk of unwanted cardiovascular events. The cannabinoids also have analgesic and anti‐inflammatory properties and reduce neuropathic pain in animal models. The present study investigated the analgesic effects of inhibiting both monoacylglycerol lipase ( MAGL ) and COX enzymes, using low doses of both inhibitors. Experimental Approach Mice subjected to chronic constriction injury ( CCI ) were tested for mechanical and cold allodynia after administration of the MAGL inhibitor, JZL184 , or the non‐selective COX inhibitor diclofenac. Then, both drugs were co‐administered at fixed dose proportions of 1:3, 1:1 and 3:1, based on their ED 50 values. PG s, endocannabinoids and related lipids were quantified in lumbar spinal cord. Key Results Combining low doses of JZL184 and diclofenac synergistically attenuated mechanical allodynia and additively reduced cold allodynia. The cannabinoid CB 1 receptor antagonist, rimonabant, but not the CB 2 receptor antagonist, SR 144528, blocked the analgesic effects of the JZL184 and diclofenac combination on mechanical allodynia, implying that CB 1 receptors were primarily responsible for the anti‐allodynia. Diclofenac alone and with JZL184 significantly reduced PG E 2 and PG F 2α in lumbar spinal cord tissue, whereas JZL184 alone caused significant increases in the endocannabinoid metabolite, N ‐arachidonoyl glycine. Conclusions and Implications Combining COX and MAGL inhibition is a promising therapeutic approach for reducing neuropathic pain with minimal side effects.