Nav1.5 expressed in TrkB+ sensory neurons mediates paclitaxel-induced mechanical pain hypersensitivity

Gomes, F. I.; Adjafre, B. L.; Lee, S.; Prudente, A.; da Silva, G.; Silva, E. A.; Kanada, L.; Roman-Campos, D.; Alves-Filho, J. C.; Cunha, F.; Waxman, S.; Dib-Hajj, S.; Berta, T.; Cunha, T. M.

doi:10.64898/2026.03.19.713015

bioRxiv · 10.64898/2026.03.19.713015

Nav1.5 expressed in TrkB+ sensory neurons mediates paclitaxel-induced mechanical pain hypersensitivity

Gomes, F. I.·Adjafre, B. L.·Lee, S.·Prudente, A.·da Silva, G.·Silva, E. A.·Kanada, L.·Roman-Campos, D.·Alves-Filho, J. C.·Cunha, F.·Waxman, S.·Dib-Hajj, S.·Berta, T.·Cunha, T. M.

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Abstract

Chemotherapy-induced neuropathic pain (CINP) is a frequent and debilitating adverse effect of anti-tumor therapies, for which current treatments are largely non-specific and offer limited efficacy. Identifying molecular mechanisms that drive CINP may enable the development of targeted therapeutic strategies. Here, we demonstrate that paclitaxel-induced mechanical pain hypersensitivity in mice occurs independently of classical Nav1.8+ nociceptors but critically depends on TrkB+ sensory neurons. Transcriptomic analysis of TrkB+ sensory neurons revealed selective expression of Scn5a, which encodes the voltage-gated sodium channel Nav1.5, a channel classically associated with cardiac excitability. Importantly, SCN5A expression was also detected in human primary sensory neurons, indicating potential translational relevance. Functional studies further showed that Scn5a knockdown, using small interfering RNA, significantly attenuates paclitaxel-induced mechanical pain hypersensitivity. Together, these findings identify TrkB+ sensory neurons as key drivers of CINP and reveal Nav1.5 as a previously unrecognized contributor to chemotherapy-induced neuropathic pain. Targeting Nav1.5 in TrkB+ sensory neurons may therefore represent a novel therapeutic strategy for the treatment of CINP.

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Gomes, F. I., Adjafre, B. L., Lee, S., Prudente, A., da Silva, G., Silva, E. A., Kanada, L., Roman-Campos, D., Alves-Filho, J. C., Cunha, F., Waxman, S., Dib-Hajj, S., Berta, T., Cunha, T. M.. 2026-03-23. Nav1.5 expressed in TrkB+ sensory neurons mediates paclitaxel-induced mechanical pain hypersensitivity. https://doi.org/10.64898/2026.03.19.713015

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