Blockers of Wnt3a, Wnt10a, or β-Catenin Prevent Chemotherapy-Induced Neuropathic Pain In Vivo

Chemotherapy remains a cornerstone of cancer treatment, yet many chemotherapeutic agents cause chronic neuropathic pain, referred to as chemotherapy-induced neuropathic pain (CINP), which often limits their therapeutic use. Currently, no medication is available to prevent CINP in cancer patients or survivors. This study investigated whether inhibitors of the canonical Wnt signaling pathway could prevent CINP. Neuropathic pain was induced in male Sprague-Dawley rats and male Axin2-LacZ knock-in mice through intraperitoneal injections of paclitaxel (PAC) administered on four alternating days. Wnt/β-catenin inhibitors, including XAV-939, LGK-974, and iCRT14, were delivered intraperitoneally as single or multiple doses, either pre- or post-injury. Mechanical allodynia was assessed using von Frey filaments, while phosphoproteomics, reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical analysis were used to evaluate phosphoproteome changes, Wnt ligand expression, inflammatory mediators, and β-catenin localization in dorsal root ganglia (DRG) from rats and humans.

Phosphoproteome profiling in CINP rats revealed significant phosphorylation changes in Wnt signaling components. Notably, repeated systemic administration of XAV-939 or LGK-974 effectively prevented CINP development in rats. Additionally, XAV-939, LGK-974, and iCRT14 mitigated established CINP. PAC treatment increased the expression of Wnt3a and Wnt10a, activated β-catenin in DRG, and elevated levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-1β (IL-1β) in DRG tissue. PAC also upregulated Axin2 expression in mice. Immunohistochemical analysis demonstrated β-catenin localization in neurons, including calcitonin gene-related peptide (CGRP)-expressing neurons, and in satellite cells within rat and human DRG. These findings suggest that chemotherapy activates Wnt signaling pathways in DRG, with pharmacological inhibition of Wnt3a, Wnt10a, and β-catenin offering a potential strategy for the prevention and treatment of CINP.