Sun Yufang, Tao Yu, Cao Junping, Zhang Yaqun, Huang Zitong, Wang Shoupeng, Lu Weiwei, Zhu Qi, Shan Lidong, Jiang Dongsheng, Zhang Yuan, Tao Jin
Department of Geriatrics, Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Department of Physiology and Neurobiology, Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou 215123, China.
J Neurosci. 2025 Jan 1;45(1):e0607242024. doi: 10.1523/JNEUROSCI.0607-24.2024.
Although the therapeutic potential of microRNA-mediated gene regulation has been investigated, its precise functional regulatory mechanism in neuropathic pain remains incompletely understood. In this study, we elucidate that miR-216a-3p serves as a critical noncoding RNA involved in the modulation of trigeminal-mediated neuropathic pain. By conducting RNA-seq and qPCR analysis, we observed a notable decrease of miR-216a-3p in the injured trigeminal ganglia (TG) of male rats. Intra-TG administration of miR-216a-3p agomir or lentiviral-mediated overexpression of miR-216a-3p specifically in sensory neurons of injured TGs alleviated established neuropathic pain behaviors, while downregulation of miR-216a-3p (pharmacologically or genetically) in naive rats induced pain behaviors. Moreover, nerve injury significantly elevated the histone H3 lysine-27 (H3K27) trimethylation (H3K27me3) levels in the ipsilateral TG, thereby suppressing the SRY-box TF 10 (SOX10) binding to the promoter and resulting in the reduction of miR-216a-3p. Inhibiting the enzymes responsible for catalyzing H3K27me3 restored the nerve injury-induced reduction in miR-216a-3p expression and markedly ameliorated neuropathic pain behaviors. Furthermore, miR-216a-3p targeted stromal interaction molecule 1 (STIM1), and the decreased miR-216a-3p associated with neuropathic pain caused a significant upregulation in the protein abundance of STIM1. Conversely, overexpression of miR-216a-3p in the injured TG suppressed the upregulation of STIM1 expression and reversed the mechanical allodynia. Together, the mechanistic understanding of H3K27me3-dependent SOX10/miR-216a-3p/STIM1 signaling axial in sensory neurons may facilitate the discovery of innovative therapeutic strategies for neuropathic pain management.
尽管已经对微小RNA介导的基因调控的治疗潜力进行了研究，但其在神经性疼痛中精确的功能调节机制仍未完全阐明。在本研究中，我们阐明了miR-216a-3p作为一种关键的非编码RNA参与三叉神经介导的神经性疼痛的调节。通过进行RNA测序和定量聚合酶链反应分析，我们观察到雄性大鼠受伤的三叉神经节（TG）中miR-216a-3p显著减少。向TG内注射miR-216a-3p激动剂或通过慢病毒介导在受伤TG的感觉神经元中特异性过表达miR-216a-3p可减轻已建立的神经性疼痛行为，而在未受伤的大鼠中下调miR-216a-3p（通过药理学或遗传学方法）会诱发疼痛行为。此外，神经损伤显著提高了同侧TG中组蛋白H3赖氨酸-27（H3K27）三甲基化（H3K27me3）水平，从而抑制了SRY盒转录因子10（SOX10）与启动子的结合，导致miR-216a-3p减少。抑制负责催化H3K27me3的酶可恢复神经损伤诱导的miR-216a-3p表达降低，并显著改善神经性疼痛行为。此外，miR-216a-3p靶向基质相互作用分子1（STIM1），与神经性疼痛相关的miR-216a-3p减少导致STIM1蛋白丰度显著上调。相反，在受伤的TG中过表达miR-216a-3p可抑制STIM1表达的上调并逆转机械性异常性疼痛。总之，对感觉神经元中H3K27me3依赖性SOX10/miR-216a-3p/STIM1信号轴的机制理解可能有助于发现用于神经性疼痛管理的创新治疗策略。
