Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Anesthesiology, Affiliated hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China; Department of Neurobiology, Parker University, Dallas, Texas.
Center of Clinical research and translational medicine, Lianyungang oriental hospital, Lianyungang, Jiangsu, China.
J Pain. 2018 Feb;19(2):186-195. doi: 10.1016/j.jpain.2017.10.003. Epub 2017 Dec 12.
Glial cell hyperactivity has been proposed to be responsible for chronic pain, however, the mechanisms remain unclear. Interleukin (IL)-18, released from glial cells, has been reported to be involved in neuropathic pain. In this study, we investigated the role of IL-18 in bone cancer pain. Bone cancer pain was mimicked by injecting Walker-256 mammary gland carcinoma cells into the intramedullary space of the tibia in rats. Expression and location of IL-18 and the IL-18 receptor were tested. To investigate the contribution of IL-18 signaling to bone cancer pain, IL-18 binding protein and recombinant IL-18 were used. To investigate the mechanisms of glial cells effects, MK801, N-methyl-D-aspartate (NMDA) receptor inhibitor, and Src kinase-specific inhibitor PP1 were used. Tumor cell implantation (TCI) treatment increased expression of IL-18 and IL-18 receptor in spinal cord. The time course of IL-18 upregulation was correlated with TCI-induced pain behaviors. Blocking the IL-18 signaling pathway prevented and reversed bone cancer-related pain behaviors. Meanwhile, blocking IL-18 signaling also suppressed TCI-induced glial cell hyperactivity, as well as activation of GluN2B and subsequent Ca-dependent signaling. Spinal administration of recombinant IL-18 in naive rat induced significant mechanical allodynia, as well as GluN2B activation. However, intrathecal injection of MK801 failed to suppress recombinant IL-18-induced GluN2B phosphorylation, whereas Src kinase inhibitor PP1 significantly inhibited IL-18-induced GluN2B activation. IL-18-mediated glial-glia and glial-neuron interaction may facilitate bone cancer pain. Blocking IL-18 signaling may effectively prevent and/or suppress bone cancer pain.
IL-18 signaling may be a new target for cancer pain therapy.
探讨白细胞介素（IL）-18 在骨癌痛中的作用。
将 Walker-256 乳腺癌细胞注入大鼠胫骨骨髓腔，模拟骨癌痛。检测 IL-18 及其受体的表达和定位。使用 IL-18 结合蛋白和重组 IL-18 研究 IL-18 信号通路对骨癌痛的贡献。使用 MK801（NMDA 受体抑制剂）和 Src 激酶特异性抑制剂 PP1 研究小胶质细胞的作用机制。
肿瘤细胞植入（TCI）治疗后脊髓中 IL-18 和 IL-18 受体表达增加。IL-18 的上调时间与 TCI 诱导的痛行为相关。阻断 IL-18 信号通路可预防和逆转骨癌相关痛行为。同时，阻断 IL-18 信号通路也抑制了 TCI 诱导的小胶质细胞过度活跃以及 GluN2B 的激活和随后的 Ca 依赖性信号转导。在未处理的大鼠鞘内给予重组 IL-18 可诱导明显的机械性痛觉过敏以及 GluN2B 的激活。然而，鞘内注射 MK801 未能抑制重组 IL-18 诱导的 GluN2B 磷酸化，而 Src 激酶抑制剂 PP1 则显著抑制 IL-18 诱导的 GluN2B 激活。
IL-18 介导的胶质细胞-胶质细胞和胶质细胞-神经元相互作用可能促进骨癌痛。阻断 IL-18 信号可能有效预防和/或抑制骨癌痛。
IL-18 信号可能成为癌症疼痛治疗的新靶点。
