{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:33:21Z","timestamp":1787045601738,"version":"build-2736575974"},"reference-count":116,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Spinal cord stimulation (SCS) is a widely used neuromodulatory therapy for chronic neuropathic pain, yet the cellular and molecular mechanisms underlying its clinical efficacy remain incompletely understood. This review synthesizes current literature on the neurophysiology of pain transmission and the mechanistic basis of major SCS paradigms (tonic, high-frequency, burst, and closed-loop stimulation), highlighting how each modality engages distinct dorsal horn circuits, glial and inflammatory pathways, as well as supraspinal networks involved in the affective dimension of pain. Particular attention is given to the evoked compound action potential (ECAP) as an emerging electrophysiological biomarker that enables real-time, feedback-guided stimulation and offers insight into the biophysical determinants of dorsal column activation. We also examine preclinical and clinical evidence linking SCS to modulation of central sensitization, neuroinflammatory signaling, and autonomic regulation, while identifying persistent gaps in mechanistic understanding. Finally, we discuss future directions, including AI-assisted, personalized SCS programming and expanding indications beyond classical neuropathic pain, underscoring the need for multimodal experimental approaches to more precisely define how SCS achieves analgesia.<\/jats:p>","DOI":"10.3390\/ijms27167373","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:06:41Z","timestamp":1787044001000},"page":"7373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular and Cellular Mechanisms of Spinal Cord Stimulation: Linking Dorsal Horn Circuits, Glia, and ECAP-Guided Therapy"],"prefix":"10.3390","volume":"27","author":[{"given":"Milan","family":"Patel","sequence":"first","affiliation":[{"name":"New York Institute of Technology, College of Osteopathic Medicine, Arkansas State University, Jonesboro, AR 72401, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1477-2072","authenticated-orcid":false,"given":"Alison","family":"Deng","sequence":"additional","affiliation":[{"name":"Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6318-3472","authenticated-orcid":false,"given":"Ameya","family":"Belamkar","sequence":"additional","affiliation":[{"name":"School of Medicine, Indiana University, Indianapolis, IN 46202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8227-1864","authenticated-orcid":false,"given":"Jamal","family":"Hasoon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Texas Health Science Center at Houston, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2464-0187","authenticated-orcid":false,"given":"Alan D.","family":"Kaye","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, School of Medicine, Louisiana State University, Shreveport, LA 71103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alaa","family":"Abd-Elsayed","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1126\/science.150.3699.971","article-title":"Pain mechanisms: A new theory","volume":"150","author":"Melzack","year":"1965","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1155\/2015\/865487","article-title":"The golden anniversary of Melzack and Wall\u2019s gate control theory of pain: Celebrating 50 years of pain research and management","volume":"20","author":"Katz","year":"2015","journal-title":"Pain Res. 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