Yamada Akihiro, Yamada Ayaka I, Ling Jennifer, Gu Jianguo G
Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294, United States of America.
Mol Brain. 2025 Jun 17;18(1):52. doi: 10.1186/s13041-025-01223-9.
Vincristine is an important chemotherapy drug to treat various types of cancer, but it induces peripheral neuropathy, leading to numbness and mechanical allodynia in the hands and feet of patients. The peripheral neuropathy is a dose-limiting toxicity of vincristine chemotherapy. How vincristine treatment causes numbness and mechanical allodynia remains incompletely understood. In the present study, we utilized Nav1.8-ChR2 transgenic mice in which Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors could be characterized using the opto-electrophysiological method. Nav1.8-ChR2-negative Aβ- and Aδ-fiber mechanoreceptors are primarily low-threshold mechanoreceptors (LTMRs). On the other hand, Nav1.8-ChR2-positive Aβ- and Aδ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (HTMRs). We have shown that the mechanical threshold of Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, but not Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors, were increased significantly in the animals treated with vincristine. In contrast, the mechanical threshold of Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors were significantly reduced following vincristine treatment. Vincristine treatment did not significantly affect the mechanical sensitivity of Nav1.8-ChR2-positive Aδ- and C-fiber mechanoreceptors. Vincristine treatment also did not affect the opto-sensitivity of Nav1.8-ChR2-positive Aβ-, Aδ-, and C-fiber mechanoreceptors. Our findings suggest that mechanical sensitivity is decreased in Aβ-fiber LTMRs and increased in Aβ-HTMRs following vincristine treatment, providing insights into vincristine-induced numbness and mechanical allodynia.
长春新碱是一种治疗多种癌症的重要化疗药物，但它会诱发周围神经病变，导致患者手脚麻木和机械性异常性疼痛。周围神经病变是长春新碱化疗的剂量限制性毒性。长春新碱治疗如何导致麻木和机械性异常性疼痛仍未完全清楚。在本研究中，我们利用了Nav1.8-ChR2转基因小鼠，其中Nav1.8-ChR2阳性和Nav1.8-ChR2阴性的机械感受器可用光电子生理学方法进行表征。Nav1.8-ChR2阴性的Aβ和Aδ纤维机械感受器主要是低阈值机械感受器（LTMRs）。另一方面，Nav1.8-ChR2阳性的Aβ和Aδ纤维机械感受器主要是高阈值机械感受器（HTMRs）。我们已经表明，在用长春新碱治疗的动物中，Nav1.8-ChR2阴性的Aβ纤维机械感受器的机械阈值显著增加，但Nav1.8-ChR2阴性的Aδ纤维机械感受器没有。相反，长春新碱治疗后，Nav1.8-ChR2阳性的Aβ纤维机械感受器的机械阈值显著降低。长春新碱治疗对Nav1.8-ChR2阳性的Aδ和C纤维机械感受器的机械敏感性没有显著影响。长春新碱治疗也不影响Nav1.8-ChR2阳性的Aβ、Aδ和C纤维机械感受器的光敏感性。我们的研究结果表明，长春新碱治疗后，Aβ纤维LTMRs的机械敏感性降低，Aβ-HTMRs的机械敏感性增加，这为长春新碱诱发的麻木和机械性异常性疼痛提供了见解。
