Department of Anaesthesiology, The University of Hong Kong, Hong Kong, China.
Laboratory and Clinical Research Institute for Pain, Department of Anaesthesiology, The University of Hong Kong, Hong Kong, China.
Pain. 2018 Mar;159(3):526-539. doi: 10.1097/j.pain.0000000000001125.
A strong link between histone deacetylases (HDACs) and nociceptive hypersensitivity has been indicated in different pain models. However, the underlying molecular and cellular mechanisms remain elusive. Here, we discovered that partial sciatic nerve ligation-induced mechanical allodynia and thermal hyperalgesia in mice were associated with increased mRNA and protein expressions of HDAC5 (a member of class IIa HDACs) and SRY-related HMG-box 10 (SOX10) in the ipsilateral lumbar dorsal horn. Gene knockdown of spinal HDAC5 or SOX10 attenuated partial sciatic nerve ligation-induced nociceptive hypersensitivity, companied with decrease of spinal neuronal sensitization markers, namely phosphorylated-Erk, phosphorylated-GluN1 (ser896), and c-Fos. Conversely, overexpression of spinal HDAC5 or SOX10 by lentiviruses in naive mice not only induced pain-like behaviors but also increased the expression of these spinal neuronal sensitization markers. Of note, in contrast to its conventional deacetylation effect to silence gene expression, overexpression of HDAC5 not only enhanced SOX10 expression but also induced nociceptive hypersensitivity in naive mice, which were reversed by SOX10 gene knockdown. Chromatin-immunoprecipitation assay further confirmed a novel nonhistone modulation function of HDACs on SOX10 expression, that is, HDAC5 regulates SOX10 by binding to the promoter region of Sox10 gene. In conclusion, this study for the first time demonstrates that HDAC5 regulates spinal neuronal sensitization in neuropathic pain by upregulating modulating SOX10 expression. Thus, interventions that reduce HDAC5/SOX10 expression may represent promising avenues in the treatment of neuropathic pain.
组蛋白去乙酰化酶（HDACs）与伤害性感受敏化之间存在很强的联系，这在不同的疼痛模型中都得到了证实。然而，其潜在的分子和细胞机制仍不清楚。在这里，我们发现，小鼠坐骨神经部分结扎引起的机械性痛觉过敏和热痛觉过敏与同侧腰椎背角中 HDAC5（IIa 类 HDACs 的一个成员）和 Sry 相关的高迁移率族盒 10（SOX10）的 mRNA 和蛋白表达增加有关。脊髓 HDAC5 或 SOX10 的基因敲低减弱了坐骨神经部分结扎引起的伤害性感受敏化，伴随着脊髓神经元敏化标志物的减少，即磷酸化-Erk、磷酸化-GluN1（ser896）和 c-Fos。相反，通过慢病毒在未处理的小鼠中过表达脊髓 HDAC5 或 SOX10，不仅引起类似疼痛的行为，还增加了这些脊髓神经元敏化标志物的表达。值得注意的是，与传统的去乙酰化作用沉默基因表达不同，HDAC5 的过表达不仅增强了 SOX10 的表达，而且在未处理的小鼠中引起了伤害性感受敏化，这种敏化可以通过 SOX10 基因敲低来逆转。染色质免疫沉淀分析进一步证实了 HDACs 在 SOX10 表达上的一种新型非组蛋白调节功能，即 HDAC5 通过与 Sox10 基因启动子区域结合来调节 SOX10 的表达。总之，这项研究首次表明，HDAC5 通过上调调节 SOX10 的表达来调节神经病理性疼痛中的脊髓神经元敏化。因此，减少 HDAC5/SOX10 表达的干预措施可能是治疗神经病理性疼痛的有前途的途径。
