Liang Lingli, Zhao Jian-Yuan, Kathryn Ticehurst, Bekker Alex, Tao Yuan-Xiang
Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Department of Cell Biology & Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
Transl Perioper Pain Med. 2019;6(4):106-114. doi: 10.31480/2330-4871/097. Epub 2019 Aug 14.
Genetic knockdown or knockout of the histone methytransferase G9a in the injured dorsal root ganglion (DRG) has been shown to alleviate neuropathic pain development. However, the application of genetic strategy in clinic is highly limited. The present study sought to examine the effect of intrathecal BIX01294, a specific G9a inhibitor, on the development and maintenance of pain hypersensitivities caused by unilateral L5 spinal nerve injury (SNL) or chronic constriction injury (CCI) to the sciatic nerve in rats. We found that intrathecal administration of BIX01294 reduced SNL- or CCI-induced mechanical allodynia, thermal hyperalgesia and cold allodynia not only in the development period but also in the maintenance period. These effects were dose-dependent. Intrathecal administration of BIX01294 also blocked the SNL-induced increase in the level of H3K9me2, a marker of G9a activity, and reversed SNL-induced downregulation of mRNA, mRNA, mRNA, mRNA, and mRNA, the downstream targets of G9a, in the ipsilateral L5 DRG. These findings further implicate that G9a as a potential target in the management of neuropathic pain.
已证实，在受损背根神经节（DRG）中对组蛋白甲基转移酶G9a进行基因敲低或敲除可减轻神经性疼痛的发展。然而，基因策略在临床上的应用非常有限。本研究旨在检测鞘内注射特异性G9a抑制剂BIX01294对大鼠单侧L5脊神经损伤（SNL）或坐骨神经慢性压迫损伤（CCI）所致疼痛超敏反应的发生和维持的影响。我们发现，鞘内注射BIX01294不仅在疼痛超敏反应的发展期，而且在维持期均能减轻SNL或CCI诱导的机械性异常性疼痛、热痛觉过敏和冷异常性疼痛。这些效应呈剂量依赖性。鞘内注射BIX01294还可阻断SNL诱导的G9a活性标志物H3K9me2水平升高，并逆转SNL诱导的同侧L5 DRG中G9a下游靶点mRNA、mRNA、mRNA、mRNA和mRNA的下调。这些发现进一步表明，G9a是治疗神经性疼痛的潜在靶点。
