Department of Anesthesiology and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX, United States.
Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
Pain. 2022 May 1;163(5):923-935. doi: 10.1097/j.pain.0000000000002454.
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.
Toll 样受体 4（TLR4）在背根神经节（DRG）和脊髓中的激活导致紫杉醇相关的化疗诱导性周围神经病（CIPN）的产生。在这里测试了 TLR4 信号在奥沙利铂诱导的 CIPN 中的普遍性。奥沙利铂处理后第 1 天雄性 SD 大鼠出现机械性超敏反应，第 14 天达到最大强度，第 35 天仍持续存在。Western blot 显示，奥沙利铂处理后第 1 天和第 7 天，DRG 中 TLR4 表达增加。用来自球形红杆菌的 TLR4 拮抗剂脂多糖或非特异性免疫抑制剂米诺环素与奥沙利铂共同处理大鼠，与接受奥沙利铂加生理盐水载体的大鼠相比，在第 7 天和第 14 天，痛觉过敏明显减轻。DRG 的免疫染色显示，在奥沙利铂处理后第 7 天和第 14 天，表达 TLR4 的神经元数量及其典型下游信号分子髓样分化初级反应基因 88（MyD88）和 TIR 结构域包含接头诱导干扰素-β增加。这些增加被来自球形红杆菌的脂多糖或米诺环素的共同处理所阻断。双染色显示 TLR4、MyD88 和 TIR 结构域包含接头诱导干扰素-β在 DRG 神经元的亚群中的定位。最后，在观察 2 周时，雄性和雌性大鼠的奥沙利铂诱导的机械性超敏反应之间没有显著差异。此外，在奥沙利铂处理后 14 天检测到 TLR4 的上调。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的 CIPN 的共同机制。
