{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:27Z","timestamp":1785428247432,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,20]]},"group-title":"Neuroscience","reference-count":36,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["CA273001"],"award-info":[{"award-number":["CA273001"]}]},{"name":"NIH","award":["CA208765"],"award-info":[{"award-number":["CA208765"]}]},{"name":"NIH","award":["DC016328"],"award-info":[{"award-number":["DC016328"]}]},{"award":["383428"],"award-info":[{"award-number":["383428"]}],"id":[{"id":"https:\/\/ror.org\/00k0a6x92","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000090","name":"CDMRP","doi-asserted-by":"crossref","award":["RH220042"],"award-info":[{"award-number":["RH220042"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Paclitaxel-induced peripheral neuropathy (PIPN) is the most common dose-limiting side effect of paclitaxel chemotherapy, yet the relationship between structural damage to peripheral nerve terminals and functional impairment of nociceptors has not been directly examined. Here we combined\n                  <jats:italic>ex vivo<\/jats:italic>\n                  skin-nerve electrophysiology with three-dimensional (3D) imaging of fDISCO-cleared glabrous skin to characterize both morphological and functional changes in peripheral sensory terminals following paclitaxel treatment in rats. Five weeks after paclitaxel administration, skin-nerve recordings revealed a marked increase in the proportion of C- and A\u03b4-fibers exhibiting spontaneous discharge (approximately 2.4- and 2.6-fold increases, respectively) compared to vehicle-treated controls. Paclitaxel also selectively reduced the mechanical activation threshold of C-fibers without affecting A\u03b4 fibers. Three-dimensional reconstruction of PGP9.5-immunolabeled nerve terminals showed that sensory fibers in glabrous skin form a vertically oriented, tree-like architecture. Paclitaxel treatment severely reduced both the terminal branch length and the density of free nerve endings in the epidermis. Strikingly, co-administration of the Kv7 channel activator retigabine prevented both the electrophysiological and morphological alterations induced by paclitaxel. These findings provide direct evidence that peripheral nerve terminal degeneration and hyperexcitability co-occur in PIPN and that Kv7 channel activation can protect against both structural and functional damage.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>This study provides the first direct evidence linking intraepidermal sensory terminal degeneration with peripheral sensory fiber hyperexcitability in paclitaxel-induced peripheral neuropathy by combining skin\u2013nerve electrophysiology with three-dimensional imaging of sensory terminals. Paclitaxel induces distal degeneration of intraepidermal sensory terminals, increases spontaneous discharge, and lowers the mechanical activation threshold of C-fibers, demonstrating that structural degeneration and functional abnormalities occur concurrently in the peripheral terminal. Retigabine prevents both structural and functional alterations, supporting peripheral sensory terminals as a therapeutic target for preventing chemotherapy-induced neuropathy.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.15.738514","type":"posted-content","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T05:50:17Z","timestamp":1784613017000},"source":"Crossref","is-referenced-by-count":0,"title":["Peripheral sensory terminal degeneration is linked to sensory fiber hyperexcitability in paclitaxel-induced peripheral neuropathy"],"prefix":"10.64898","author":[{"given":"Junhui","family":"Du","sequence":"first","affiliation":[{"name":"Department of Neurobiology, University of Texas Medical Branch, Galveston, TX 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3892-9208","authenticated-orcid":false,"given":"Abdi","family":"Salahadin","sequence":"additional","affiliation":[{"name":"Department of Pain 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