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Traditional models of structural degeneration and inflammation inadequately explain the clinical discordance between tissue damage and pain severity. This review explores the paradigm shift in understanding tendinopathic pain, elucidating the transition from a simple mechanical stress model to a complex neuroplastic disorder. We narratively review the multilayered pathophysiological mechanisms underlying chronic tendinopathic pain. Specifically, we outline abnormal mechanical load transduction, peripheral neuroimmune\u2013vascular coupling, and central nervous system (CNS) remodeling. Abnormal mechanical overload initially activates mechanosensitive ion channels, transducing physical stress into biochemical nociceptive signals. Subsequently, chronic immune responses and neurovascular coupling drive peripheral sensitization, which is further amplified by aberrant sensory neoinnervation and neuroimmune crosstalk. Furthermore, CNS involvement manifests as spinal\u2010level central sensitization and maladaptive remodeling of the motor cortex. Managing chronic tendinopathic pain requires transcending the traditional focus on localized structural lesions. Future strategies should prioritize precise clinical phenotyping, targeted pharmacotherapy, and neuroplasticity\u2010informed rehabilitation to optimize patient outcomes.<\/jats:p>","DOI":"10.1155\/prm\/1712265","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:14:12Z","timestamp":1789557252000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathological Mechanisms of Tendinopathy Pain: From Mechanical Overload to Neuroimmune\u2013Vascular Crosstalk"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-0441-2852","authenticated-orcid":false,"given":"Chenyu","family":"He","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6284-643X","authenticated-orcid":false,"given":"Hongbo","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6640-1374","authenticated-orcid":false,"given":"Hewei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD006355.pub2"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD003525.pub2"},{"key":"e_1_2_9_3_2","first-page":"1351","article-title":"Systematic Review of the Efficacy and Safety of Shock Wave Therapy for Lateral Elbow Pain","volume":"33","author":"Buchbinder R.","year":"2006","journal-title":"Journal of Rheumatology"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsm.2006.030916"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1186\/scrt426"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.324.7338.626"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2019-100885"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.3810\/psm.2000.05.890"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.1177\/03635465000280040901"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kep384"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.surge.2017.04.004"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202506440"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.766080"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2017-000456"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2070"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11916-024-01299-3"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00167-003-0391-6"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001590"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2014-094386"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjsports-2015-095215"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/ard.53.6.359"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.3109\/03008207809152283"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/iep.12027"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300601RRR"},{"key":"e_1_2_9_25_2","first-page":"593","article-title":"Tendon Cells in Vivo Form a Three Dimensional Network of Cell Processes Linked by Gap Junctions","volume":"189","author":"McNeilly C. 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