治疗骨癌疼痛 (BCP) 仍然是一个临床挑战，并且 BCP 的潜在机制仍然难以捉摸。这项研究报告称，背根神经节神经元中的 Wnt5a/Ryk 信号传导对于 BCP 的发展至关重要。胫骨骨腔肿瘤细胞植入会产生自发的和诱发的行为表达疼痛以及神经体和外周末梢以及受肿瘤影响的骨组织中的异位发芽和 Wnt5a/Ryk 信号传导活性。足底内、胫骨内或鞘内注射 Wnt5a/Ryk 信号阻断剂可显着抑制疼痛症状。在幼稚大鼠中外周注射外源性 Wnt5a 会产生疼痛，并且背根神经节神经元对 Wnt5a 变得更加敏感。 Wnt5a/Ryk 信号传导激活增加细胞内钙反应和瞬时受体潜在香草酸 1 型的表达，并调节辣椒素诱导的细胞内钙反应。阻断 Ryk 受体激活可抑制 Wnt5a 诱导的机械异常性疼痛和热痛觉过敏。通过抑制 c-Jun N 末端激酶激活，可以阻断 Wnt5a 促进瞬时受体潜在的香草酸 1 型致敏作用。这些发现表明Wnt5a/Ryk信号传导是BCP发病机制的一个关键外周机制，并表明针对初级感觉神经元和肿瘤侵袭区域的Wnt5a/Ryk可能是预防和治疗BCP的有效方法。 2024 年国际疼痛研究协会。

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.Copyright © 2024 International Association for the Study of Pain.