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

Abstract

Abstract Objective 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 (GABA RVM neurons) facilitate nociceptive transmission by inhibiting off-cells activity. This research examined the role of GABA RVM neurons in the analgesic effects of EA. Methods 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. Results 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 GABA RVM neurons. Also, EA reduced the calcium activity, neuronal firing rates, and c-Fos expression of GABA RVM neurons in both pain models. Chemogenetic inhibition of GABA RVM neurons increased nociceptive thresholds. Chemogenetic activation of GABA RVM 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 GABA RVM neurons counteracted the analgesic effects of EA in CFA and CCI-induced pain models. Conclusions The study indicates that the analgesic effect of EA in inflammatory and neuropathic pain is facilitated by CB1 receptor-mediated inhibition of GABA RVM neurons. Graphical Abstracts

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