Microglia’s Phenotypic Heterogeneity in Pain Pathogenesis and Electroacupuncture Analgesia: Mechanisms and Therapeutic Potential

Dingru Ji,1,* Zhengyi Lyu,2,* Shannah Erasmus,3,* Yuxin Wu,1 Xingzhen Li,1 Xue Chen,1 Junfan Fang,1 Junying Du,1 Jianqiao Fang,1 Jie Zhou,4 Yi Liang1 1Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2Department of Acupuncture and Chinese Tuina, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 3International Education College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Liang, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +86 0571-86633328, Fax +86 571-86658056, Email [email protected] Jie Zhou, Department of Acupuncture and Moxibustion, The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China, Tel +8615968895450, Fax +86 0571-88393516, Email [email protected]: Pain is a complex physiological phenomenon driven by dynamic microglial(MG) regulation in the CNS. Aberrant microglial activation mediates neuroinflammation, neuronal hyperexcitability, and synaptic plasticity, exhibiting spatiotemporal and sex-specific heterogeneity. While early pharmacological interventions show time-limited efficacy, electroacupuncture (EA) emerges as a potent non-pharmacological strategy that disrupts microglia-neuron crosstalk via multiple pathways. Critically, EA’s efficacy depends on intervention timing, with early application preventing microglial active in neuropathic models. Recent advances reveal CD11c+ microglia as dual regulators of pain resolution and relapse—clearing myelin debris acutely but driving recurrence via MMP-9-mediated synaptic remodeling. This review synthesizes microglial heterogeneity, stage-specific interventions, and EA’s translational potential in rebalancing microglial phenotypes for precision pain management.Keywords: microglia, pain, morphology, polarization, inflammation