The cannabinoid receptor 1 suppresses neuropeptide Y transcription in the peripheral nervous system to mediate analgesia.

Cannabinoid receptor 1 (CB1) mediate cannabinoid-induced analgesia, yet CB1-targeted therapies show poor clinical efficacy against neuropathic pain . The present study aimed to elucidate the molecular mechanism of CB1-mediated analgesia in sensory neurons and to identify potential therapeutic targets. We established a chronic constriction injury (CCI) model in male mice and evaluated pain-related behaviors using von Frey filament and hot plate tests. Transcriptome sequencing was performed to screen differentially expressed genes in the dorsal root ganglia (DRG) following CB1 conditional KO and nerve injury, with key differentially expressed geness validated by quantitative polymerase chain reaction and immunofluorescence. The transcriptional interaction between activating transcription factor 3 (ATF3) and neuropeptide Y (NPY) was further verified using chromatin immunoprecipitation analysis-quantitative polymerase chain reaction and luciferase reporter assays. We demonstrated that sensory neuronal CB1 plays a vital analgesic role under both physiological and neuropathic conditions. CCI-induced CB1 downregulation in the DRG impairs the analgesic efficacy of CB1 agonists. Genetic deletion of CB1 in sensory neuron activates ATF3 and NPY transcription, causing persistent hyperalgesia. After nerve injury, the expression of CB1 is suppressed in DRG, while the transcription of ATF3 and NPY is activated. ATF3 translocates into the nucleus and subsequently drives the transcription of NPY. Consistently, silencing ATF3 or NPY effectively alleviated hyperalgesia induced by CCI or CB1 conditional KO. Collectively, our results indicate that CB1 may exert analgesic effects by indirectly inhibiting the ATF3/NPY signaling cascade. Targeting ATF3/NPY signaling provides a promising alternative therapeutic strategy for neuropathic pain, overcoming the clinical limitations of conventional CB1 agonists.