Combined inhibition of monoacylglycerol lipase and cyclooxygenases synergistically reduces neuropathic pain in mice.
OBJECTIVE
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.


METHODS
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 ED50 values. PGs, endocannabinoids and related lipids were quantified in lumbar spinal cord.


RESULTS
Combining low doses of JZL184 and diclofenac synergistically attenuated mechanical allodynia and additively reduced cold allodynia. The cannabinoid CB1 receptor antagonist, rimonabant, but not the CB2 receptor antagonist, SR144528, blocked the analgesic effects of the JZL184 and diclofenac combination on mechanical allodynia, implying that CB1 receptors were primarily responsible for the anti-allodynia. Diclofenac alone and with JZL184 significantly reduced PGE2 and PGF2α in lumbar spinal cord tissue, whereas JZL184 alone caused significant increases in the endocannabinoid metabolite, N-arachidonoyl glycine.


CONCLUSIONS
Combining COX and MAGL inhibition is a promising therapeutic approach for reducing neuropathic pain with minimal side effects.
Department of Psychology, West Virginia University, Morgantown, WV, USA.
Molly S
MS
Crowe
Emma
E
Leishman
Matthew L
ML
Banks
Ramesh
R
Gujjar
Anu
A
Mahadevan
Heather B
HB
Bradshaw
Steven G
SG
Kinsey
D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D052117:Benzodioxoles / Q000627:therapeutic use*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004008:Diclofenac / Q000627:therapeutic use*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015777:Eicosanoids / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant; D013116:Spinal Cord / Q000378:metabolism
D000700:Analgesics; D052117:Benzodioxoles; D063387:Cannabinoid Receptor Antagonists; D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D063388:Endocannabinoids; D005227:Fatty Acids; C534333:JZL 184; D010880:Piperidines; D011720:Pyrazoles; D004008:Diclofenac; D011451:Prostaglandin-Endoperoxide Synthases; D008994:Monoacylglycerol Lipases; D000077285:Rimonabant