{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:03:24Z","timestamp":1782975804064,"version":"3.54.5"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Tuina, a traditional Chinese non-pharmacological therapy, is effective in treating neuropathic pain (NP). However, its underlying molecular mechanisms remain elusive. The degradation of perineuronal nets (PNNs) via the CX3CL1\/CX3CR1 axis is a key driver of central sensitization. This study investigates whether Tuina exerts analgesia by modulating this specific neuro-immune axis to preserve PNNs integrity in a rat model of chronic compression of the dorsal root ganglion (CCD).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Sprague\u2013Dawley rats were subjected to CCD surgery to establish the NP model. To validate the role of PNNs, a subset of rats received intrathecal chondroitinase ABC (chABC). To explore Tuina\u2019s mechanism, rats were divided into Sham, Model, Tuina, CX3CR1 inhibitor (AZD8797), and Tuina + AZD8797 groups. Standardized Tuina intervention or inhibitor administration was performed from days 4 to 14 post-surgery. Pain behaviors (PWT and PWL) were evaluated. Spinal dorsal horn tissues were analyzed using transmission electron microscopy, Western blotting, immunofluorescence, and flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CCD induced severe mechanical allodynia and thermal hyperalgesia, accompanied by the structural disruption of spinal PNNs\u2014indicated by a significant loss of WFA-binding glycosaminoglycans despite unchanged total aggrecan core protein levels\u2014and ultrastructural neuronal damage. Mechanistically, CCD upregulated the CX3CL1\/CX3CR1\/PI3K\/AKT cascade, which was associated with increased markers of microglial phagocytosis (upregulated TREM2 and LAMP1), as well as Ca\n                      <jats:sup>2+<\/jats:sup>\n                      influx and c-FOS accumulation. Tuina intervention attenuated these pathological alterations, significantly restoring WFA expression and suggesting a preservation of PNNs structural integrity. Furthermore, the combined treatment (Tuina + AZD8797) yielded an enhanced analgesic and biochemical recovery compared to either monotherapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tuina produces robust central analgesia by suppressing the CX3CL1\/CX3CR1-PI3K\/AKT signaling pathway. This suppression restores microglial phagocytic homeostasis and crucially protects the glycosaminoglycan lattice of PNNs against excessive degradation, thereby alleviating neuropathic central sensitization.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1860375","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:35:54Z","timestamp":1782970554000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Tuina therapy alleviates neuropathic pain by modulating the CX3CL1\/CX3CR1 axis to inhibit degradation of the perineuronal nets"],"prefix":"10.3389","volume":"19","author":[{"given":"Yukui","family":"Tian","sequence":"first","affiliation":[{"name":"School of Traditional Chinese Medicine, Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Institute of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingguang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Institute of Tuina, Shanghai Academy of Traditional Chinese Medicine","place":["Shanghai, China"]},{"name":"Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gulaisar","family":"Aikebaier","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Cui","sequence":"additional","affiliation":[{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Tuina, Shanghai Academy of Traditional Chinese Medicine","place":["Shanghai, China"]},{"name":"Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junchang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Traditional Chinese Medicine, Xinjiang Medical University","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]},{"name":"Institute of Traditional Chinese Medicine of Xinjiang Uygur Autonomous Region","place":["\u00dcr\u00fcmqi, Xinjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"eabg1601","DOI":"10.1126\/sciadv.abg1601","article-title":"Microglial dyshomeostasis drives perineuronal net and synaptic loss in a CSF1R(+\/\u2212) mouse model of ALSP, which can be rescued via CSF1R inhibitors","volume":"7","author":"Arreola","year":"2021","journal-title":"Sci. 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