Cannabinoid CB1 Receptor Regulates Spinal Dorsal Horn Synaptic Plasticity in a Mouse Model of Neuropathic Pain through the CB1R/SREBP1/NAMPT/SIRT1 Metabolic Regulatory Framework.

backgroundNeuropathic pain is sustained by maladaptive synaptic plasticity in the spinal dorsal horn. Increasing evidence suggests that metabolic regulation is closely linked to synaptic function, as lipid metabolism, membrane microdomain organization, NAD

methodsA chronic constriction injury (CCI) mouse model was used. Mice were treated with the CB1R antagonist AM251 or the CB1R agonist WIN55,212-2. Mechanical and thermal hypersensitivity, C-fiber-evoked long-term potentiation in the spinal dorsal horn, plasma lipid indices, and the expression of CB1R, SREBP1, NAMPT, and SIRT1 were assessed.

resultsCB1R activation alleviated CCI-induced mechanical and thermal hypersensitivity and attenuated exaggerated C-fiber-evoked spinal long-term potentiation, whereas CB1R inhibition produced the opposite tendency. AM251 reduced spinal dorsal horn CB1R, SREBP1, and NAMPT protein levels by 49.0%, 37.8%, and 57.5%, respectively, compared with untreated CCI mice, while increasing SIRT1 protein by 17.8% (p < 0.01). In contrast, WIN55,212-2 increased CB1R, SREBP1, and NAMPT protein levels by 24.5%, 23.7%, and 17.2%, respectively, and reduced SIRT1 protein by 28.8% compared with untreated CCI mice (p < 0.01). qPCR analysis showed consistent changes at the transcriptional level.

conclusionCB1R activation is associated with pain relief, suppression of spinal synaptic potentiation, and coordinated regulation of the SREBP1/NAMPT/SIRT1 metabolic axis. These findings suggest that CB1R-mediated metabolic regulation may contribute to maladaptive spinal synaptic plasticity in neuropathic pain.