Sex-dependent endocannabinoid adaptations in supraspinal pain modulatory circuits after peripheral nerve injury

Abstract

Peripheral nerve injury produces persistent pain-related behaviours that differ between sexes, but whether chronic neuropathic pain is accompanied by sex-dependent alterations in endocannabinoid signalling across pain-modulatory circuits remains unclear. We quantified endocannabinoids and related N-acylethanolamines and expression of cannabinoid receptors and metabolic enzymes across supraspinal and spinal regions 100 days after spared nerve injury (SNI) in male and female rats. SNI increased 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA) in the prefrontal cortex and 2-AG in the rostral ventromedial medulla in males, with exploratory associations between these measures and reduced pain-related hypersensitivity. In females, SNI increased monoacylglycerol lipase expression in the periaqueductal grey. Additional sex- and hemisphere-dependent differences in ECS components were observed in limbic regions,whereas no significant injury-related changes were detected in spinal cord or plasma. These findings identify regionally distinct ECS alterations during established neuropathic pain and suggest that chronic nerve injury is associated with different patterns of supraspinal ECS plasticity in males and females.