Sex-dependent endocannabinoid adaptations in supraspinal pain-modulatory circuits after peripheral nerve injury
Year: 2026
Type: preprint
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. Perspective This study identifies sex- and region-dependent alterations in endocannabinoid signalling during established neuropathic pain. Distinct changes in supraspinal pain-modulatory regions in male and female rats highlight biological sex as an important consideration when investigating the endocannabinoid system as a therapeutic target for chronic neuropathic pain.
Language: English
Subfield: Pharmacology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Irish Research Council
Award: G3177715451
OpenAlex ID: W7222471768