• Su Liu, Yue-Peng Liu, You Lv, Jun-Li Yao, Dong-Mei Yue, Mao-Yin Zhang, Dun-Yi Qi, and Gong-Jian Liu.
• 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. Electronic address: liusu08@gmail.com.
• J Pain. 2018 Feb 1; 19 (2): 186-195.

AbstractGlial 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 Ca2+-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.Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

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