Du Lixia, Zhu Jianyu, Liu Shenbin, Yang Wei, Hu Xueming, Zhang Wenwen, Cui Wenqiang, Yang Yayue, Wang Chenghao, Yang Yachen, Gao Tianchi, Zhang Chen, Zhang Ruofan, Lou Mengping, Zhou Hong, Rao Jia, Maoying Qiliang, Chu Yuxia, Wang Yanqing, Mi Wenli
Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Biochemistry, School of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Pain. 2025 Feb 1;166(2):347-359. doi: 10.1097/j.pain.0000000000003346. Epub 2024 Aug 8.
Cold allodynia is a common complaint of patients suffering from neuropathic pain initiated by peripheral nerve injury. However, the mechanisms that drive neuropathic cold pain remain elusive. In this study, we show that the interleukin (IL)-33/ST2 signaling in the dorsal root ganglion (DRG) is a critical contributor to neuropathic cold pain by interacting with the cold sensor transient receptor potential melastatin 8 (TRPM8). By using the St2-/- mice, we demonstrate that ST2 is required for the generation of nociceptor hyperexcitability and cold allodynia in a mouse model of spared nerve injury (SNI). Moreover, the selective elimination of ST2 function from the Nav1.8-expressing nociceptor markedly suppresses SNI-induced cold allodynia. Consistent with the loss-of-function studies, intraplantar injection of recombinant IL-33 (rIL-33) is sufficient to induce cold allodynia. Mechanistically, ST2 is co-expressed with TRPM8 in both mouse and human DRG neurons and rIL-33-induced Ca 2+ influx in mouse DRG neurons through TRPM8. Co-immunoprecipitation assays further reveal that ST2 interacts with TRPM8 in DRG neurons. Importantly, rIL-33-induced cold allodynia is abolished by pharmacological inhibition of TRPM8 and genetic ablation of the TRPM8-expressing neurons. Thus, our findings suggest that the IL-33/ST2 signaling mediates neuropathic cold pain through downstream cold-sensitive TRPM8 channels, thereby identifying a potential analgesic target for the treatment of neuropathic cold pain.
冷痛觉过敏是外周神经损伤引发的神经性疼痛患者的常见主诉。然而，引发神经性冷痛的机制仍不清楚。在本研究中，我们发现背根神经节（DRG）中的白细胞介素（IL）-33/ST2信号通路通过与冷感受器瞬时受体电位香草酸亚型8（TRPM8）相互作用，成为神经性冷痛的关键促成因素。通过使用St2基因敲除小鼠，我们证明在 spared nerve injury（SNI）小鼠模型中，ST2是伤害感受器兴奋性过高和冷痛觉过敏产生所必需的。此外，从表达Nav1.8的伤害感受器中选择性消除ST2功能可显著抑制SNI诱导的冷痛觉过敏。与功能丧失研究一致，足底注射重组IL-33（rIL-33）足以诱导冷痛觉过敏。机制上，ST2在小鼠和人类DRG神经元中均与TRPM8共表达，并且rIL-33通过TRPM8诱导小鼠DRG神经元中的Ca²⁺内流。免疫共沉淀分析进一步揭示ST2在DRG神经元中与TRPM8相互作用。重要的是，TRPM8的药理学抑制和表达TRPM8的神经元的基因消融消除了rIL-33诱导的冷痛觉过敏。因此，我们的研究结果表明，IL-33/ST2信号通路通过下游冷敏感的TRPM8通道介导神经性冷痛，从而确定了一个治疗神经性冷痛的潜在镇痛靶点。
