Although chemotherapy is a key cancer treatment, many chemotherapeutic drugs produce chronic neuropathic pain, called chemotherapy-induced neuropathic pain (CINP), which is a dose-limiting adverse effect. To date, there is no medicine that prevents CINP in cancer patients and survivors. We determined whether blockers of the canonical Wnt signaling pathway prevent CINP. Neuropathic pain was induced by intraperitoneal injection of paclitaxel (PAC) on four alternate days in male Sprague-Dawley rats or male Axin2-LacZ knock-in mice. XAV-939, LGK-974, and iCRT14, Wnt/β-catenin blockers, were administered intraperitoneally as a single or multiple doses before or after injury. Mechanical allodynia, phosphoproteome profiling, Wnt ligands, and inflammatory mediators were measured by von Frey filament, phosphoproteomics, reverse transcription-polymerase chain reaction, and Western blot analysis. Localization of β-catenin was determined by immunohistochemical analysis in the dorsal root ganglia (DRGs) in rats and human. Our phosphoproteome profiling of CINP rats revealed significant phosphorylation changes in Wnt signaling components. Importantly, repeated systemic injections of XAV-939 or LGK-974 prevented the development of CINP in rats. In addition, XAV-939, LGK-974, and iCRT14 ameliorated CINP. PAC increased Wnt3a and Wnt10a, activated β-catenin in DRG, and increased monocyte chemoattractant protein-1 and interleukin-1β in DRG. PAC also upregulated rAxin2 in mice. Furthermore, β-catenin was expressed in neurons, including calcitonin gene–related protein-expressing neurons and satellite cells in rat and human DRG. In conclusion, chemotherapy increases Wnt3a, Wnt10a, and β-catenin in DRG and their pharmacological blockers prevent and ameliorate CINP, suggesting a target for the prevention and treatment of CINP.

尽管化疗是一种关键的癌症治疗方法，但许多化疗药物会产生慢性神经性疼痛，称为化疗引起的神经性疼痛 (CINP)，这是一种剂量限制性副作用。迄今为止，还没有药物可以预防癌症患者和幸存者的 CINP。我们确定了经典 Wnt 信号通路的阻滞剂是否会阻止 CINP。在雄性 Sprague-Dawley 大鼠或雄性Axin2-LacZ 中隔四天腹膜内注射紫杉醇 (PAC) 诱导神经性疼痛敲入小鼠。XAV-939、LGK-974 和 iCRT14、Wnt/β-连环蛋白阻滞剂在损伤前后以单剂量或多剂量腹膜内给药。机械性异常性疼痛、磷酸化蛋白质组分析、Wnt 配体和炎症介质通过 von Frey 细丝、磷酸化蛋白质组学、逆转录-聚合酶链反应和蛋白质印迹分析进行测量。β-连环蛋白的定位是通过免疫组织化学分析在大鼠和人类的背根神经节 (DRG) 中确定的。我们对 CINP 大鼠的磷酸化蛋白质组分析揭示了 Wnt 信号成分的显着磷酸化变化。重要的是，反复全身注射 XAV-939 或 LGK-974 可防止大鼠发生 CINP。此外，XAV-939、LGK-974 和 iCRT14 改善了 CINP。PAC 增加 Wnt3a 和 Wnt10a，激活 DRG 中的 β-catenin，并增加 DRG 中的单核细胞趋化蛋白-1 和白细胞介素-1β。PAC 还上调了小鼠的 rAxin2。此外，β-连环蛋白在神经元中表达，包括大鼠和人 DRG 中的降钙素基因相关蛋白表达神经元和卫星细胞。总之，化疗增加了 DRG 中的 Wnt3a、Wnt10a 和 β-catenin，它们的药理阻滞剂可以预防和改善 CINP，为预防和治疗 CINP 提供了一个靶点。