Activation of toll-like receptor 4 (TLR4) in the dorsal root ganglion (DRG) and spinal cord contributes to the generation of paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Generalizability of TLR4 signaling in oxaliplatin-induced CIPN was tested here. Mechanical hypersensitivity developed in male SD rats by day 1 after oxaliplatin treatment, reached maximum intensity by day 14, and persisted through day 35. Western blot revealed an increase in TLR4 expression in the DRG of oxaliplatin at days 1 and 7 after oxaliplatin treatment. Cotreatment of rats with the TLR4 antagonist lipopolysaccharide derived from Rhodobacter sphaeroides ultrapure or with the nonspecific immunosuppressive minocycline with oxaliplatin resulted in significantly attenuated hyperalgesia on day 7 and 14 compared with rats that received oxaliplatin plus saline vehicle. Immunostaining of DRGs revealed an increase in the number of neurons expressing TLR4, its canonical downstream signal molecules myeloid differentiation primary response gene 88 (MyD88) and TIR-domain–containing adapter-inducing interferon-β, at both day 7 and day 14 after oxaliplatin treatment. These increases were blocked by cotreatment with either lipopolysaccharide derived from Rhodobacter sphaeroides or minocycline. Double staining showed the localization of TLR4, MyD88, and TIR-domain–containing adapter-inducing interferon-β in subsets of DRG neurons. Finally, there was no significant difference in oxaliplatin-induced mechanical hypersensitivity between male and female rats when observed for 2 weeks. Furthermore, upregulation of TLR4 was detected in both sexes when tested 14 days after treatment with oxaliplatin. These findings suggest that the activation of TLR4 signaling in DRG neurons is a common mechanism in CIPN induced by multiple cancer chemotherapy agents.

背根神经节 (DRG) 和脊髓中 Toll 样受体 4 (TLR4) 的激活导致紫杉醇相关化疗引起的周围神经病变(CIPN)的产生。此处测试了 TLR4 信号传导在奥沙利铂诱导的 CIPN 中的普遍性。雄性 SD 大鼠在奥沙利铂治疗后第 1 天出现机械超敏反应，在第 14 天达到最大强度，并持续到第 35 天。蛋白质印迹显示奥沙利铂治疗后第 1 天和第 7 天奥沙利铂 DRG 中 TLR4 表达增加。与接受奥沙利铂加盐水载体的大鼠相比，用来自超纯球形红杆菌的 TLR4拮抗剂脂多糖或非特异性免疫抑制米诺环素与奥沙利铂共同治疗大鼠，第 7 天和第 14 天的痛觉过敏显着减弱。DRGs 免疫染色显示，在奥沙利铂治疗后第 7 天和第 14 天，表达 TLR4 的神经元数量增加，其典型下游信号分子骨髓分化初级反应基因 88 (MyD88) 和包含 TIR 结构域的接头诱导干扰素-β治疗。这些增加可以通过与球形红杆菌衍生的脂多糖或米诺环素共同治疗来阻止。双重染色显示 TLR4、MyD88 和包含 TIR 结构域的接头诱导干扰素-β 在 DRG 神经元亚群中的定位。最后，观察2周后，雄性和雌性大鼠之间奥沙利铂诱导的机械超敏反应没有显着差异。此外，在奥沙利铂治疗 14 天后进行测试时，两性中均检测到 TLR4 上调。这些发现表明，DRG 神经元中 TLR4 信号的激活是多种癌症化疗药物诱导 CIPN 的常见机制。