{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:19:31Z","timestamp":1788326371219,"version":"build-2803163510"},"reference-count":113,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007300","name":"China Medical University","doi-asserted-by":"crossref","award":["CMU112-MF-24"],"award-info":[{"award-number":["CMU112-MF-24"]}],"id":[{"id":"10.13039\/501100007300","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Science and Technology Council, Taiwan","award":["NSTC 113-2320-B-039-052-MY3"],"award-info":[{"award-number":["NSTC 113-2320-B-039-052-MY3"]}]},{"name":"Chinese Medicine Research Center of China Medical University via the Higher Education Sprout Project (Featured Areas Research Center Program) from the Ministry of Education, Taiwan","award":["CMRC-CENTER-3"],"award-info":[{"award-number":["CMRC-CENTER-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background: Neuropathic pain (NP) is a debilitating chronic condition driven by maladaptive neuroimmune interactions in the spinal cord, with microglia playing a central pathological role. Electroacupuncture (EA) has shown analgesic effects in clinical and preclinical studies, but the microglia-centered mechanisms underlying these effects remain incompletely integrated. This review aims to provide a comprehensive mechanistic synthesis of how EA modulates microglia-associated neuroinflammatory pathways in neuropathic pain. Methods: This systematic search-narrative review used systematic search and screening procedures to identify English-language animal studies published between 2015 and 2025 in PubMed, CINAHL, Web of Science, and Cochrane Library. Twenty-six animal studies investigating EA effects on microglia-associated signaling pathways in neuropathic pain models met the inclusion criteria. Because of substantial heterogeneity in neuropathic pain models, EA parameters, molecular endpoints, and behavioral outcomes, findings were synthesized narratively, and no meta-analysis was performed. Results: The reviewed evidence revealed four convergent mechanistic categories through which EA modulates microglial activity: (1) attenuation of purinergic microglial activation via downregulation of IRF8, P2X4R, P2X7R; (2) suppression of innate immune sensing and inflammasome pathways, including TLR4\/MyD88\/NF-\u03baB and NLRP3 signaling; (3) inhibition of downstream inflammatory amplification through p38 MAPK, PI3K\/AKT, and COX-2 pathways; and (4) promotion of pro-resolution mechanisms involving IL-10\/\u03b2-endorphin, PD-L1, GRK2\/TREM2\/DAP12, \u03b17nAChR, GLP-1R, and GABAergic signaling. Conclusions: The available preclinical evidence suggests that EA modulates multiple microglia-associated pathways, attenuating inflammatory signaling while enhancing selected pro-resolution mechanisms. These findings provide a mechanistic framework for understanding EA-induced analgesia in neuropathic pain and highlight microglial signaling networks as important targets for future experimental and translational investigation.<\/jats:p>","DOI":"10.3390\/brainsci16090914","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:47:13Z","timestamp":1787849233000},"page":"914","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanisms of Electroacupuncture-Induced Spinal Microglial Reprogramming in Neuropathic Pain: A Systematic Search\u2013Narrative Review"],"prefix":"10.3390","volume":"16","author":[{"given":"Boon Khai","family":"Teoh","sequence":"first","affiliation":[{"name":"Graduate Institute of Acupuncture Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trang Thi Hoai","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Chinese Medicine, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"},{"name":"Faculty of Traditional Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 90000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotha","family":"Peddanna","sequence":"additional","affiliation":[{"name":"Graduate Institute of Acupuncture Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6328-3692","authenticated-orcid":false,"given":"Tran Van Bao","family":"Quach","sequence":"additional","affiliation":[{"name":"Graduate Institute of Acupuncture Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"},{"name":"Faculty of Traditional Medicine, Can Tho University of Medicine and Pharmacy, Can Tho 90000, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3642-8047","authenticated-orcid":false,"given":"Jaung-Geng","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Acupuncture Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8946-7939","authenticated-orcid":false,"given":"Yi-Hung","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Acupuncture Science, China Medical University, No. 91, Hsueh-Shih Road, Taichung 404328, Taiwan"},{"name":"International Master Program in Integrative Health, China Medical University, Taichung 404328, Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 404328, Taiwan"},{"name":"Department of Computer Science and Information Engineering, Asia University, Taichung 413305, Taiwan"},{"name":"Office of Research & Development, Asia University, Taichung 413305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1097\/j.pain.0000000000001939","article-title":"The revised International Association for the Study of Pain definition of pain: Concepts, challenges, and compromises","volume":"161","author":"Raja","year":"2020","journal-title":"Pain"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/S1474-4422(14)70251-0","article-title":"Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis","volume":"14","author":"Finnerup","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104232","DOI":"10.1016\/j.lpm.2024.104232","article-title":"Neuropathic pain: Evidence based recommendations","volume":"53","author":"Moisset","year":"2024","journal-title":"La Presse M\u00e9dicale"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1093\/pm\/pnz075","article-title":"A Comprehensive Algorithm for Management of Neuropathic Pain","volume":"20","author":"Bates","year":"2019","journal-title":"Pain Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"E3441","DOI":"10.1073\/pnas.1602070113","article-title":"Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation","volume":"113","author":"Grace","year":"2016","journal-title":"Proc. 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