NFAT1 Signaling Contributes to Bone Cancer Pain by Regulating IL-18 Expression in Spinal Microglia

IF 4.8 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-02-17 DOI:10.1111/cns.70222

Xuetai Chen, Ying Zeng, Zizhu Wang, Jixiang Zhu, Fengyun Liu, Mingxuan Zhu, Jiayi Zheng, Qingdaiyao Chen, Dongxu Zhai, Yangyang Chen, Jiayao Niu, Zhouya Xue, Guan Sun, Feng Li, Zhiqiang Pan

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Abstract

Aims

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.

Methods

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.

Results

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 Ca²⁺-dependent signaling.

Conclusion

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.

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.