Department of Physiology and Neurobiology, Medical College of Soochow University, Suzhou 215123, People's Republic of China.
Centre for Ion Channelopathy, Medical College of Soochow University, Suzhou 215123, People's Republic of China.
Proc Natl Acad Sci U S A. 2022 Apr 5;119(14):e2117209119. doi: 10.1073/pnas.2117209119. Epub 2022 Mar 30.
microRNA (miRNA)–mediated gene regulation has been studied as a therapeutic approach, but its functional regulatory mechanism in neuropathic pain is not well understood. Here, we identify that miRNA-32-5p (miR-32-5p) is a functional RNA in regulating trigeminal-mediated neuropathic pain. High-throughput sequencing and qPCR analysis showed that miR-32-5p was the most down-regulated miRNA in the injured trigeminal ganglion (TG) of rats. Intra-TG injection of miR-32-5p agomir or overexpression of miR-32-5p by lentiviral delivery in neurons of the injured TG attenuated established trigeminal neuropathic pain. miR-32-5p overexpression did not affect acute physiological pain, while miR-32-5p down-regulation in intact rats was sufficient to cause pain-related behaviors. Nerve injury increased the methylated histone occupancy of binding sites for the transcription factor glucocorticoid receptor in the miR-32-5p promoter region. Inhibition of the enzymes that catalyze H3K9me2 and H3K27me3 restored the expression of miR-32-5p and markedly attenuated pain behaviors. Further, miR-32-5p–targeted Cav3.2 T-type Ca2+ channels and decreased miR-32-5p associated with neuropathic pain caused an increase in Cav3.2 protein expression and T-type channel currents. Conversely, miR-32-5p overexpression in injured TG suppressed the increased expression of Cav3.2 and reversed mechanical allodynia. Together, we conclude that histone methylation-mediated miR-32-5p down-regulation in TG neurons regulates trigeminal neuropathic pain by targeting Cav3.2 channels.
微小 RNA（miRNA）介导的基因调控已被研究作为一种治疗方法，但它在神经病理性疼痛中的功能调节机制尚不清楚。在这里，我们确定 miRNA-32-5p（miR-32-5p）是调节三叉神经介导的神经性疼痛的功能性 RNA。高通量测序和 qPCR 分析显示，miR-32-5p 是大鼠损伤三叉神经节（TG）中下调最明显的 miRNA。TG 内注射 miR-32-5p 激动剂或通过慢病毒转染在损伤 TG 的神经元中过表达 miR-32-5p 可减轻已建立的三叉神经病理性疼痛。miR-32-5p 过表达不会影响急性生理疼痛，而在完整大鼠中下调 miR-32-5p 足以引起与疼痛相关的行为。神经损伤增加了 miR-32-5p 启动子区域结合转录因子糖皮质激素受体的组蛋白 H3K9me2 和 H3K27me3 的甲基化占有率。抑制催化 H3K9me2 和 H3K27me3 的酶恢复了 miR-32-5p 的表达，并显著减轻了疼痛行为。此外，miR-32-5p 靶向 Cav3.2 T 型 Ca2+通道，并降低与神经病理性疼痛相关的 miR-32-5p，导致 Cav3.2 蛋白表达和 T 型通道电流增加。相反，在损伤 TG 中过表达 miR-32-5p 抑制 Cav3.2 的表达增加，并逆转机械性痛觉过敏。综上所述，我们得出结论，TG 神经元中组蛋白甲基化介导的 miR-32-5p 下调通过靶向 Cav3.2 通道调节三叉神经病理性疼痛。
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