2. Academic Validation
  3. Specific inhibition of TET1 in the spinal dorsal horn alleviates inflammatory pain in mice by regulating synaptic plasticity

Specific inhibition of TET1 in the spinal dorsal horn alleviates inflammatory pain in mice by regulating synaptic plasticity

  • Neuropharmacology. 2023 Nov 24:109799. doi: 10.1016/j.neuropharm.2023.109799.
Kehui Yang 1,  Runa Wei 1,  Qiaoqiao Liu 1,  Yang Tao 1,  Zixuan Wu 1,  Li Yang 1,  Qi-Hui Wang 1,  Hongjun Wang 2,  Zhiqiang Pan 3
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: wanghon0490@sina.com.
  • 3 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. Electronic address: zhiqiangp2002@aliyun.com.
PMID: 38008374 DOI: 10.1016/j.neuropharm.2023.109799
Abstract

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 Tet1fl/fl 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.

Keywords

CFA; Dendritic spine; Inflammatory pain; Synaptic plasticity; TET1.

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