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<p>Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (<i>Nt3</i>) mRNA and its encoded proneurotrophin-3 (proNT3) protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking this upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking paclitaxel-induced upregulation of DRG proNT3 produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, proNT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (<i>Ccl2</i>) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that <i>Nt3</i> mRNA co-expresses with TrkC and <i>Ccl2</i> mRNAs in DRG neurons, proNT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. Thus, proNT3 may be a potential target for CINP treatment.</p>

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Proneurotrophin-3 contributes to chemotherapy-induced neuropathic pain through TrkC-mediated CCL2 elevation in DRG neurons

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Dilip Sharma,
  • Xiaozhou Feng,
  • Bing Wang,
  • Huijie Shang,
  • Bushra Yasin,
  • Alex Bekker,
  • Huijuan Hu,
  • Yuan-Xiang Tao

摘要

Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and its encoded proneurotrophin-3 (proNT3) protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking this upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking paclitaxel-induced upregulation of DRG proNT3 produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, proNT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, proNT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. Thus, proNT3 may be a potential target for CINP treatment.