Yang Kehui, Wei Runa, Liu Qiaoqiao, Tao Yang, Wu Zixuan, Yang Li, Wang Qi-Hui, Wang Hongjun, Pan Zhiqiang
Jiangsu Province Key Laboratory of Anesthesiology, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
Jiangsu Province Key Laboratory of Anesthesiology, China; Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, China; NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
Neuropharmacology. 2024 Feb 15;244:109799. doi: 10.1016/j.neuropharm.2023.109799. Epub 2023 Nov 25.
DNA demethylation mediated by ten-eleven translocation 1 (TET1) is a critical epigenetic mechanism in which gene expression is regulated via catalysis of 5-methylcytosine to 5-hydroxymethylcytosine. Previously, we demonstrated that TET1 is associated with the genesis of chronic inflammatory pain. However, how TET1 participates in enhanced nociceptive responses in chronic pain remains poorly understood. Here, we report that conditional knockout of Tet1 in dorsal horn neurons via intrathecal injection of rAAV-hSyn-Cre in Tet1 mice not only reversed the inflammation-induced upregulation of synapse-associated proteins (post-synaptic density protein 95 (PSD95) and synaptophysin (SYP)) in the dorsal horn but also ameliorated abnormalities in dendritic spine morphology and alleviated pain hypersensitivities. Pharmacological blockade of TET1 by intrathecal injection of a TET1-specific inhibitor-Bobcat 339-produced similar results, as did knockdown of Tet1 by intrathecal injection of siRNA. Thus, our data strongly suggest that increased TET1 expression during inflammatory pain upregulates the expression of multiple synapse-associated proteins and dysregulates synaptic morphology in dorsal horn neurons, suggesting that Tet1 may be a potential target for analgesic strategies.
由十一锌指蛋白1（TET1）介导的DNA去甲基化是一种关键的表观遗传机制，通过催化5-甲基胞嘧啶转化为5-羟甲基胞嘧啶来调节基因表达。此前，我们证明TET1与慢性炎性疼痛的发生有关。然而，TET1如何参与慢性疼痛中伤害性反应的增强仍知之甚少。在此，我们报告，通过向Tet1小鼠鞘内注射rAAV-hSyn-Cre有条件地敲除背角神经元中的Tet1，不仅逆转了炎症诱导的背角中突触相关蛋白（突触后致密蛋白95（PSD95）和突触素（SYP））的上调，还改善了树突棘形态异常并减轻了疼痛超敏反应。鞘内注射TET1特异性抑制剂Bobcat 339对TET1进行药理学阻断产生了类似的结果，鞘内注射siRNA敲低Tet1也产生了类似结果。因此，我们的数据强烈表明，炎性疼痛期间TET1表达增加会上调多种突触相关蛋白的表达并使背角神经元的突触形态失调，这表明Tet1可能是镇痛策略的潜在靶点。
