Wnt5a/Ryk signaling contributes to bone cancer pain by sensitizing the peripheral nociceptors through JNK-mediated TRPV1 pathway in rats.

Abstract

Treating bone cancer pain (BCP) continues to be a clinical challenge, and the underlying mechanisms of BCP remain elusive. This study reports that Wnt5a/Ryk signaling in the dorsal root ganglion neurons is critical to the development of BCP. Tibia bone cavity tumor cell implantation produces spontaneous and evoked behaviorally expressed pain as well as ectopic sprouting and activity of Wnt5a/Ryk signaling in the neural soma and peripheral terminals and the tumor-affected bone tissues. Intraplantar, intratibial, or intrathecal injection of Wnt5a/Ryk signaling blockers significantly suppresses the painful symptoms. Peripheral injection of exogenous Wnt5a in naïve rats produces pain, and the dorsal root ganglion neurons become more sensitive to Wnt5a. Wnt5a/Ryk signaling activation increases intracellular calcium response and expression of transient receptors potential vanilloid type-1 and regulates capsaicin-induced intracellular calcium response. Blocking Ryk receptor activation suppresses Wnt5a-induced mechanical allodynia and thermal hyperalgesia. Wnt5a facilitation of transient receptors potential vanilloid type-1 sensitization is blocked by inhibiting c-Jun N-terminal kinase activation. These findings indicate a critical peripheral mechanism of Wnt5a/Ryk signaling underlying the pathogenesis of BCP and suggest that targeting Wnt5a/Ryk in the primary sensory neurons and the tumor-invasive area may be an effective approach for the prevention and treatment of BCP.