Wu Bin, Su Xiaolin, Zhang Wentong, Zhang Yi-Hong, Feng Xinghua, Ji Yong-Hua, Tan Zhi-Yong
Institute of Special Environment Medicine, Nantong University, Nantong, China.
Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.
Front Mol Neurosci. 2021 Jun 4;14:690858. doi: 10.3389/fnmol.2021.690858. eCollection 2021.
Use of chemotherapy drug oxaliplatin is associated with painful peripheral neuropathy that is exacerbated by cold. Remodeling of ion channels including TRP channels in dorsal root ganglion (DRG) neurons contribute to the sensory hypersensitivity following oxaliplatin treatment in animal models. However, it has not been studied if TRP channels and membrane depolarization of DRG neurons serve as the initial ionic/membrane drives (such as within an hour) that contribute to the development of oxaliplatin-induced neuropathic pain. In the current study, we studied in mice (1) acute effects of oxaliplatin on the membrane excitability of IB4 and IB4 subpopulations of DRG neurons using a perforated patch clamping, (2) the preventative effects of a membrane-hyperpolarizing drug retigabine on oxaliplatin-induced sensory hypersensitivity, and (3) the preventative effects of TRP channel antagonists on the oxaliplatin-induced membrane hyperexcitability and sensory hypersensitivity. We found (1) IB4 and IB4 subpopulations of small DRG neurons displayed previously undiscovered, substantially different membrane excitability, (2) oxaliplatin selectively depolarized IB4 DRG neurons, (3) pretreatment of retigabine largely prevented oxaliplatin-induced sensory hypersensitivity, (4) antagonists of TRPA1 and TRPM8 channels prevented oxaliplatin-induced membrane depolarization, and (5) the antagonist of TRPM8 largely prevented oxaliplatin-induced sensory hypersensitivity. These results suggest that oxaliplatin depolarizes IB4 neurons through TRPM8 channels to drive the development of neuropathic pain and targeting the initial drives of TRPM8 and/or membrane depolarization may prevent oxaliplatin-induce neuropathic pain.
化疗药物奥沙利铂的使用与因寒冷而加剧的疼痛性外周神经病变相关。包括背根神经节（DRG）神经元中的瞬时受体电位（TRP）通道在内的离子通道重塑，在动物模型中对奥沙利铂治疗后的感觉超敏反应起作用。然而，尚未研究TRP通道和DRG神经元的膜去极化是否作为促成奥沙利铂诱导的神经性疼痛发展的初始离子/膜驱动因素（例如在一小时内）。在本研究中，我们在小鼠中研究了：（1）使用穿孔膜片钳技术，奥沙利铂对DRG神经元的IB4和IB4亚群膜兴奋性的急性影响；（2）膜超极化药物瑞替加滨对奥沙利铂诱导的感觉超敏反应的预防作用；以及（3）TRP通道拮抗剂对奥沙利铂诱导的膜兴奋性过高和感觉超敏反应的预防作用。我们发现：（1）小DRG神经元的IB4和IB4亚群表现出先前未发现的、显著不同的膜兴奋性；（2）奥沙利铂选择性地使IB4 DRG神经元去极化；（3）瑞替加滨预处理在很大程度上预防了奥沙利铂诱导的感觉超敏反应；（4）TRPA1和TRPM8通道拮抗剂预防了奥沙利铂诱导的膜去极化；以及（5）TRPM8拮抗剂在很大程度上预防了奥沙利铂诱导的感觉超敏反应。这些结果表明，奥沙利铂通过TRPM8通道使IB4神经元去极化，以驱动神经性疼痛的发展，而针对TRPM8和/或膜去极化的初始驱动因素可能预防奥沙利铂诱导的神经性疼痛。
