Chen Xuetai, Zeng Ying, Wang Zizhu, Zhu Jixiang, Liu Fengyun, Zhu Mingxuan, Zheng Jiayi, Chen Qingdaiyao, Zhai Dongxu, Chen Yangyang, Niu Jiayao, Xue Zhouya, Sun Guan, Li Feng, Pan Zhiqiang
Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Department of Anesthesiology, The Yancheng Clinical College of Xuzhou Medical University, The First people's Hospital of Yancheng, Yancheng, China.
Department of Anesthesiology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
CNS Neurosci Ther. 2025 Feb;31(2):e70222. doi: 10.1111/cns.70222.
This study aimed to test the hypothesis that nuclear factor of activated T cells 1 (NFAT1) signaling contributes to bone cancer pain by regulating interleukin (IL)-18 expression in spinal microglia.
This study was performed on male mice using a Lewis lung carcinoma-induced bone cancer pain model. Nociceptive behaviors were evaluated by measuring mechanical allodynia, thermal hyperalgesia, and spontaneous pain. Expression levels were measured via real-time quantitative polymerase chain reaction, western blotting, and immunofluorescence analysis. The effect of pharmacologic intervention of spinal NFAT1/IL-18 signaling on bone cancer pain was the primary outcome.
NFAT1 expression was upregulated in the spinal microglia after tumor inoculation. Pharmacological inhibition of NFAT1 upregulation prevented and reversed bone cancer-related pain behaviors. In spinal microglia, NFAT1 inhibition decreased p38 MAPK phosphorylation and IL-18 production. Blocking NFAT1 signaling suppressed tumor-induced neuronal sensitization and microglial activation as well as activation of the N-methyl-D-aspartate receptor and the subsequent Ca-dependent signaling.
Microglia NFAT1-p38 signaling contributes to bone cancer pain through IL-18-mediated central sensitization in spinal microglia. NFAT1 could be a potential target for therapeutic intervention to prevent bone cancer pain.
本研究旨在验证活化T细胞核因子1（NFAT1）信号通过调节脊髓小胶质细胞中白细胞介素（IL）-18的表达促进骨癌痛这一假说。
本研究采用Lewis肺癌诱导的骨癌痛模型对雄性小鼠进行实验。通过测量机械性异常性疼痛、热痛觉过敏和自发痛来评估伤害性反应行为。通过实时定量聚合酶链反应、蛋白质免疫印迹法和免疫荧光分析来检测表达水平。脊髓NFAT1/IL-18信号通路的药物干预对骨癌痛的影响是主要观察指标。
接种肿瘤后脊髓小胶质细胞中NFAT1表达上调。对NFAT1上调的药物抑制可预防和逆转骨癌相关的疼痛行为。在脊髓小胶质细胞中，抑制NFAT1可降低p38丝裂原活化蛋白激酶的磷酸化水平和IL-18的产生。阻断NFAT1信号通路可抑制肿瘤诱导的神经元致敏和小胶质细胞活化，以及N-甲基-D-天冬氨酸受体的活化和随后的钙依赖性信号传导。
小胶质细胞NFAT1-p38信号通路通过IL-18介导的脊髓小胶质细胞中枢敏化作用促进骨癌痛。NFAT1可能是预防骨癌痛治疗干预的潜在靶点。
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