Electroacupuncture Ameliorates Hyperalgesia and Anxiety-Like Behaviors in Chemotherapy-Induced Peripheral Neuropathy Mice Through Inhibition of Astrocyte-Mediated Neuronal Activation in the Anterior Cingulate Cortex.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse effect of anticancer therapy and is frequently accompanied by anxiety-related symptoms. Effective preventive treatments are lacking, and available pharmacological options provide limited relief, highlighting the need for adjunctive non-pharmacological strategies in cancer care. Emerging evidence suggests that astrocyte-neuron crosstalk within the anterior cingulate cortex (ACC) contributes to chronic pain and pain-associated emotional disorders. Electroacupuncture (EA) has shown beneficial effects in CIPN; however, the central mechanisms underlying its therapeutic actions remain unclear. This study investigated whether astrocyte-mediated neuronal activation in the ACC is associated with the analgesic and anxiolytic effects of EA in CIPN. Methods: A mouse model of CIPN was established by repeated intraperitoneal administration of paclitaxel. Mice received EA or sham EA once daily for seven consecutive days. Mechanical allodynia, thermal hyperalgesia, and anxiety-like behaviors were assessed using the von Frey test, Hargreaves test, and open field test, respectively. Astrocytic and neuronal activation, GAT-1 expression, and GABA levels in the ACC were evaluated by immunofluorescence staining, Western blotting, and ELISA. Chemogenetic approaches were used to selectively activate or inhibit ACC astrocytes. Results: CIPN mice exhibited significant mechanical and thermal hypersensitivity and anxiety-like behaviors. EA significantly alleviated pain hypersensitivity and anxiety-like behaviors while suppressing astrocytic activation, downregulating GAT-1 expression, restoring GABA levels, and reducing neuronal activation. Chemogenetic inhibition of ACC astrocytes alleviated pain- and anxiety-like behaviors in CIPN mice, whereas astrocytic activation markedly attenuated the beneficial effects of EA. Conclusion: EA alleviates CIPN-induced pain hypersensitivity and anxiety-like behaviors by suppressing astrocytic activation, normalizing GAT-1 expression and GABA levels, and attenuating neuronal activation in the ACC. These findings identify astrocyte-mediated neuronal activation as a novel mechanism involved in EA-induced analgesia and a potential therapeutic target for CIPN and its associated affective comorbidities. Overall, this study provides preclinical mechanistic evidence for further evaluating EA as an adjunctive non-pharmacological approach for the integrated management of neuropathic pain and affective symptoms in patients with CIPN.