Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain

Area of Science:

• Pharmacology
• Pain Research
• Neuroscience

Background:

• Post-surgical pain is a common clinical problem with current treatments having potential adverse events with repeated use.
• Monoacylglycerol lipase (MAGL) inhibition has demonstrated analgesic properties, potentially mediated by cannabinoid receptors (CB1 or CB2), depending on the pain type.

Purpose of the Study:

• To investigate the analgesic potential of MAGL inhibition, alone and in combination with the NSAID diclofenac sodium.
• To explore the underlying mechanisms of MAGL inhibition-induced analgesia in a post-surgical pain model.

Main Methods:

• Male and female C57BL/6J mice underwent hindpaw incision (HPI) surgery.
• Evaluated mechanical allodynia, climbing, grip strength, and thermal preference 24 hours post-HPI.
• Assessed dose-dependent effects of MAGL inhibitors (JZL184, MJN110) and diclofenac, and their combined potential, using CB1/CB2 antagonists and a CB2 agonist.

Main Results:

• MAGL inhibitors (JZL184, MJN110) and diclofenac sodium attenuated HPI-induced mechanical allodynia.
• The anti-allodynic effect of JZL184 was mediated via CB2 receptors, as it was blocked by a CB2 antagonist but not a CB1 antagonist.
• Combined sub-analgesic doses of JZL184 and diclofenac sodium produced an additive analgesic effect; repeated JZL184 administration did not induce tolerance.

Conclusions:

• MAGL inhibition, particularly through CB2 receptor mechanisms, is effective in managing post-surgical pain.
• Simultaneous targeting of endocannabinoid pathways (via MAGL inhibition) and cyclooxygenase (COX) enzymes (via NSAIDs) presents a promising strategy for post-operative pain management.