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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic pain, a devastatingly prevalent condition, is increasingly understood not merely as a disorder of neuronal signaling but as a failure of the neuronal infrastructure itself. Central to this paradigm is the microtubule (MT) cytoskeleton, which functions not as a passive scaffold but as a dynamic regulatory hub and the primary railway for intracellular transport. This review provides a comprehensive mechanistic analysis of how the dysregulation of microtubule dynamics drives the initiation and maintenance of chronic pain. We dissect the change in microtubule dynamics across diverse pain etiologies, summarizing how diverse insults lead to either pathological hyper-stabilization or catastrophic disassembly of the microtubule network. Finally, we explore emerging therapeutic strategies that move beyond broad-spectrum microtubule modulators to target specific regulatory proteins such as Histone deacetylase 6 (HDAC6), Collapsin Response Mediator Protein 2 (CRMP2), Heat Shock Protein 27 (HSP27), and motor proteins (kinesins and dyneins). We propose that restoring cytoskeletal homeostasis, by which we recalibrate the tubulin code or rescue motor-driven transport, represents a paradigm-shifting approach to pain management. By moving the therapeutic focus from blocking electrical signals to repairing the structural and logistical integrity of the nociceptive neuron, these strategies hold the potential to modify the underlying disease process, offering a new frontier for analgesic development.<\/jats:p>","DOI":"10.3390\/ijms27188135","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Microtubule Cytoskeleton Dysfunction in Chronic Pain: Mechanisms of Transport Failure and Emerging Therapeutic Targets"],"prefix":"10.3390","volume":"27","author":[{"given":"Zheng","family":"Li","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiantian","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1213\/ANE.0000000000001389","article-title":"A Systematic Review and Meta-Analysis of the Global Burden of Chronic Pain Without Clear Etiology in Low- and Middle-Income Countries: Trends in Heterogeneous Data and a Proposal for New Assessment Methods","volume":"123","author":"Jackson","year":"2016","journal-title":"Anesth. 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