Locus Coeruleus Noradrenergic‐Spinal Projections Contribute to Electroacupuncture‐Mediated Antinociception in Postoperative Pain in Mice

Postoperative pain remains a significant challenge in healthcare. Electroacupuncture (EA) has gained polarity in helping manage surgical pain and showed beneficial effects on enhancing postoperative analgesia, decreasing opioid requirement. Despite this, the precise mechanisms underlying these actions are poorly understood. Evidence shows the involvement of noradrenaline (NE) in the action of EA. However, the precise identity of the NE source after EA treatment, its mechanisms of action, and the circuitry locus in the pain-regulating pathway remain elusive. It is shown that plantar incision (PI) leads to hypoactivity of noradrenergic neurons in the locus coeruleus (LC), which brings about impaired NE release in the spinal dorsal horn (SDH). EA treatment normalizes the abnormal hypoexcitability of LC noradrenergic neurons after PI and thus triggers enhanced NE release in the SDH. Optogenetic inhibition of LC noradrenergic neurons eliminates EA-induced NE release and antinociceptive effects after PI, while activation of these neurons mimics EA-induced NE release and antinociception. The resultant increased NE release after EA activates spinal α_2A-adrenoceptor and inhibits CaMKII signaling, which in turn depresses spinal excitatory neuronal hyperexcitability and eventually relieves postoperative pain. It is concluded that LC noradrenergic-spinal projections and subsequent α_2A-adrenoceptor-CaMKII signaling cascades in the SDH contribute to EA-induced antinociception in postoperative pain.