Mechanisms Of Wnt/β-catenin Signaling In The Chemotherapy-induced Neuropathic Pain

Chemotherapy drugs such as vincristine can produce painful peripheral neuropathy(chemotherapy-induced neuropathic pain,CINP)for which is the major dose-limiting factor in cancer chemotherapy.Our current understanding of the molecular mechanisms underlying CNP is still incomplete.Therefore,looking for Recent studies suggest that Wnt signaling is dysregulated in the spinal cord of bone cancer pain models et al.It is not clear whether the Wnt signaling pathways involved in CNP.This study is based on the Wnt signaling pathway to explore the pathogenesis of CNP.The results were reported as follows.(1)We first addressed whether Wnt/β-catenin signaling in the spinal cord was activated by using a mouse model of CNP.The expression of Wnt3a、phosphorylation β-catenin and dephosphorylated activeβ-catenin at the level of L4–L5 in the spinal cord of CNP mice were analysized by Western blot.Our results showed that compared with control animals,Wnt3 a 、 phosphorylation β-catenin and dephosphorylated activeβ-catenin expression was significantly increased at 11 days and 18days(P<0.05)。(2)To address whether the activation of Wnt/β-catenin signaling played a role in the CNP,intrathecal administration of the Wnt inhibitor IWR in CNP mice was performed,then behavioral experiments were done to detect the change of mechanical withdrawal threshold.The results showed that the mechanical withdrawal threshold was significantly increased in CNP mice injected with IWR compared to the vehicle group(P<0.05).(3)To address whether the Wnt/β-catenin signaling played a role in CNP through astrocytic and microglia activation,the expression of GFAP and IBA-1 in the dorsal horn were analysized by immunohistochemistry.Immunofluorescence showed that the intensity of GFAP and IBA-1 significantly increased in the dorsal horn compared with control group(P<0.05).However,the intensity of them significantly decreased in CNP animals injected with IWR compared with vehicle-treated animals(P<0.05).(4)To address whether the Wnt/β-catenin signaling played a role in CNP by regulating the expression of proinflammatory mediators which released by astrocyte and microglia respectively,the expression of TNF-α and MCP-1 in the spinal cord were analysized by ELISA.ELISA showed that the expression of TNF-α and MCP-1 significantly increased in the spinal cord compared with control group(P<0.05).Whereas the expression of them significantly decreased in CNP animals injected with IWR compared with vehicle-treated animals(P<0.05).(5)To address whether the Wnt/β-catenin signaling played a role in CNP through MAPK/ERK signaling,the expression of p-ERK at the level of L4–L5 in the spinal cord of CNP mice was analysized by Western blot.The results showed that the protein levels of p-ERK significantly increased in the spinal cord compared with control group(P<0.05).Furthemore the expression of it significantly decreased in CNP animals injected with IWR compared with vehicle-treated animals(P<0.05).In summary,the present study demonstrated that the Wnt/β-catenin signaling contributed to CNP by regulating neuroinflammation which mediated by the glia in the spinal cord.And the Wnt/β-catenin signaling might be new mechanisms of CNP and valuable drug target to CNP.