Electroacupuncture alleviates mechanical allodynia and anxiety‐like behaviors induced by chronic neuropathic pain via regulating rostral anterior cingulate cortex‐dorsal raphe nucleus neural circuit

AIMS: Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between neuropathic pain and psychiatric conditions such as anxiety. Preclinical and clinical work has demonstrated that electroacupuncture (EA) effectively alleviates anxiety‐like behaviors induced by chronic neuropathic pain. In this study, a potential neural circuitry underlying the therapeutic action of EA was investigated. METHODS: The effects of EA stimulation on mechanical allodynia and anxiety‐like behaviors in animal models of spared nerve injury (SNI) were examined. EA plus chemogenetic manipulation of glutamatergic (Glu) neurons projecting from the rostral anterior cingulate cortex (rACC(Glu)) to the dorsal raphe nucleus (DRN) was used to explore the changes of mechanical allodynia and anxiety‐like behaviors in SNI mice. RESULTS: Electroacupuncture significantly alleviated both mechanical allodynia and anxiety‐like behaviors with increased activities of glutamatergic neurons in the rACC and serotoninergic neurons in the DRN. Chemogenetic activation of the rACC(Glu)‐DRN projections attenuated both mechanical allodynia and anxiety‐like behaviors in mice at day 14 after SNI. Chemogenetic inhibition of the rACC(Glu)‐DRN pathway did not induce mechanical allodynia and anxiety‐like behaviors under physiological conditions, but inhibiting this pathway produced anxiety‐like behaviors in mice at day 7 after SNI; this effect was reversed by EA. EA plus activation of the rACC(Glu)‐DRN circuit did not produce a synergistic effect on mechanical allodynia and anxiety‐like behaviors. The analgesic and anxiolytic effects of EA could be blocked by inhibiting the rACC(Glu)‐DRN pathway. CONCLUSIONS: The role of rACC(Glu)‐DRN circuit may be different during the progression of chronic neuropathic pain and these changes may be related to the serotoninergic neurons in the DRN. These findings describe a novel rACC(Glu)‐DRN pathway through which EA exerts analgesic and anxiolytic effects in SNI mice exhibiting anxiety‐like behaviors.