| Neuropathic pain is caused by altered nerve function that often presents as allodynia, which is the painful perception of typically non-noxious stimuli. 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. However, chronic cyclooxygenase inhibition also causes gastrointestinal inflammation and increased 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. Mice subjected to the chronic constriction injury (CCI) model of neuropathic pain were administered either the MAGL inhibitor, JZL184 (1-40 mg/kg, i.p.) or the nonselective COX inhibitor diclofenac sodium (1-100 mg/kg, i.p.) and tested for mechanical and cold allodynia. Then, both drugs were coadministered at various doses in ratios of 1:3, 1:1, and 3:1 parts of either compound. Isobolographic analyses revealed that combining low doses of JZL184 and diclofenac synergistically attenuated mechanical allodynia and additively reduced cold allodynia. These data support dual COX/MAGL inhibition as a promising therapeutic approach for neuropathic pain. |
