BACKGROUND AND PURPOSE:

Neuropathic pain is commonly treated with GABA analogues, steroids, or non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs inhibit one or more cyclooxygenase (COX) enzymes and are effective, commonly used analgesics that have relatively fewer side effects than other treatments, such as immunosuppressants and steroids. However, chronic COX inhibition also increases gastrointestinal inflammation and risk of cardiac events. Like NSAIDs, cannabinoids have analgesic and anti-inflammatory properties and reduce neuropathic pain in preclinical models. The present study investigated the analgesic effects of inhibiting both monoacylglycerol lipase (MAGL) and cyclooxygenase enzymes.

EXPERIMENTAL APPROACH:

Mice subjected to chronic constriction injury (CCI) were tested for mechanical and cold allodynia after MAGL inhibitor, JZL184 or the nonselective COX inhibitor diclofenac sodium administration. Then, both drugs were coadministered at fixed dose proportions of 1:3, 1:1, and 3:1 parts based on the ED50 values of either compound. Prostaglandins, 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 receptor 1 (CB1 ) antagonist, rimonabant, but not the cannabinoid receptor 2 antagonist, SR144528, blocked the analgesic effects of the JZL184 and diclofenac combination on mechanical allodynia, thus CB1 was primarily responsible for the anti-allodynia. Diclofenac alone and with JZL184 significantly reduced prostaglandins E2 and F2α in lumbar spinal cord tissue, whereas JZL184 alone caused significant increases in the endocannabinoid metabolite, N- arachidonoyl glycine.

CONCLUSIONS AND IMPLICATIONS:

Dual COX/MAGL inhibition is a promising therapeutic approach for reducing neuropathic pain with minimal side effects.
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