Electroacupuncture produces analgesic effects via cannabinoid CB1 receptor-mediated GABAergic neuronal inhibition in the rostral ventromedial medulla

Electroacupuncture (EA) is commonly used for pain control in clinical practice, yet the precise mechanisms underlying its action are not fully understood. The rostral ventromedial medulla (RVM) plays a crucial role in the modulation of pain. GABAergic neurons in the RVM (GABARVM neurons) facilitate nociceptive transmission by inhibiting off-cells activity. This research examined the role of GABARVM neurons in the analgesic effects of EA. Nociceptive behavior was evaluated using inflammatory pain models induced by complete Freund's adjuvant (CFA) and neuropathic pain models induced by chronic constrictive injury (CCI). Also, in situ hybridization, chemogenetics, in vivo mouse calcium imaging, and in vivo electrophysiological recordings were used to determine neuronal activity and neural circuitry. EA at the "Zusanli" (ST36) on the affected side produced a significant analgesic effect in both CFA and CCI models. CFA treatment and CCI elevated the calcium activity of GABARVM neurons. Also, EA reduced the calcium activity, neuronal firing rates, and c-Fos expression of GABARVM neurons in both pain models. Chemogenetic inhibition of GABARVM neurons increased nociceptive thresholds. Chemogenetic activation of GABARVM neurons caused increased pain sensitivity in control mice and negated the analgesic effects of EA in both pain models. Moreover, reducing cannabinoid CB1 receptors on GABARVM neurons counteracted the analgesic effects of EA in CFA and CCI-induced pain models. The study indicates that the analgesic effect of EA in inflammatory and neuropathic pain is facilitated by CB1 receptor-mediated inhibition of GABARVM neurons.