Dissociable peripheral and central mechanisms of monoacylglycerol lipase inhibition on pain- and depression-related behaviors in a rat model of neuropathic pain

ABSTRACT: Chronic pain is a significant risk factor for depression, but mechanisms linking these conditions remain unclear. The endocannabinoid 2-arachidonoylglycerol, degraded by monoacylglycerol lipase (MGL), modulates both pain and mood. Although MGL inhibition enhances 2-arachidonoylglycerol signaling, its antidepressant potential in chronic pain has not been fully defined. We examined the behavioral, electrophysiological, and receptor-specific effects of the MGL inhibitor MJN110 in rats with spared nerve injury. Pain- and depression-like behaviors were assessed, and in vivo single-unit recordings were performed from dorsal root ganglion (DRG) neurons and medial prefrontal cortex (mPFC) pyramidal neurons. Cannabinoid receptors type 1 (CB1R) and 2 (CB2R) antagonists were used to determine receptor mechanisms. MJN110 produced dose-dependent differential effects on sensory and depression-related behaviors. Higher doses (1-5 mg/kg) alleviated mechanical and cold hypersensitivity via suppression of DRG nociceptor activity through peripheral CB1Rs. Both high (1 and 5 mg/kg) and low doses (0.3 mg/kg) reversed spared nerve injury-induced depression-like behaviors, including anhedonia and behavioral despair. Low-dose MJN110 normalized suppressed mPFC firing without altering nociceptive thresholds. CB1R blockade abolished both antidepressant and antinociceptive effects, whereas CB2R antagonism had only a minimal impact on antinociception. These findings suggest that MGL inhibition alleviates pain-induced depression potentially by restoring mPFC activity, even at doses insufficient to relieve sensory hypersensitivity. High-dose MGL inhibition reduces sensory hypersensitivity via activation of peripheral CB1Rs on DRG neurons. These findings identify dose- and site-specific CB1R mechanisms for separating the sensory and affective dimensions of pain and support endocannabinoid augmentation as a dual antidepressant-antinociceptive strategy in chronic pain comorbidity.