Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression
Normalizing HDAC2 Levels in the Spinal Cord Alleviates Thermal and Mechanical Hyperalgesia After Peripheral Nerve Injury and Promotes GAD65 and KCC2 Expression
复制标题
脊髓中 HDAC2 水平正常化可减轻周围神经损伤后的热痛和机械痛觉过敏，并促进 GAD65 和 KCC2 表达
DOI：
10.3389/fnins.2019.00346
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发表时间：
2019
影响因子：
4.3
通讯作者：
Yingqi Weng
中科院分区：
文献类型：
--
作者：
Bihan Ouyang;Dan Chen;Xinran Hou;Tongxuan Wang;Jian Wang;Wangyuan Zou;Zongbin Song;Changsheng Huang;Qulian Guo;Yingqi Weng
神经性疼痛是一个全球性的健康问题，治疗效果不佳。越来越多的证据表明组蛋白低乙酰化参与神经性疼痛的发生和维持。因此，许多天然和合成的组蛋白脱乙酰酶（HDAC）抑制剂经过测试，对动物神经性疼痛表现出显着的镇痛作用。然而，评估导致神经性疼痛的 HDAC 特定亚型的研究有限。在本研究中，利用慢性压迫性损伤（CCI）大鼠模型，我们发现坐骨神经损伤后大鼠腰脊髓中HDAC2的mRNA和蛋白水平增加。鞘内注射泛HDAC抑制剂TSA可以抑制HDAC2蛋白的增加，但不能抑制mRNA的增加，并表现出剂量依赖性的镇痛作用。通过慢病毒载体将 HDAC2 特异性 shRNA 引入脊髓，我们证实 HDAC2 介导神经损伤后的机械和热痛觉过敏。进一步检查发现中枢神经系统抑制回路中神经病理性疼痛的两个重要参与者：HDAC2敲除后CCI大鼠脊髓中的GAD65和KCC2增加。因此，我们的研究证实HDAC2参与周围神经损伤引起的机械和热痛觉过敏。此外，GAD65 和 KCC2 是 HDAC2 在疼痛调节途径中可能的下游靶标。
Neuropathic pain is a worldwide health concern with poor treatment outcomes. Accumulating evidence suggests that histone hypoacetylation is involved in development and maintenance of neuropathic pain. Thus, many natural and synthetic histone deacetylase (HDACs) inhibitors were tested and exhibited a remarkable analgesic effect against neuropathic pain in animals. However, studies evaluating specific subtypes of HDACs contributing to neuropathic pain are limited. In this study, using the chronic constriction injury (CCI) rat model, we found that mRNA and protein levels of HDAC2 were increased in the lumbar spinal cord of rats after sciatic nerve injury. Intrathecal injection of TSA, a pan-HDAC inhibitor, suppressed the increase in HDAC2 protein but not mRNA, and showed a dose-dependent pain-relieving effect. By introducing HDAC2-specific shRNA into the spinal cord via a lentivirus vector, we confirmed that HDAC2 mediates mechanical and thermal hyperalgesia after nerve injury. Further examination found two essential participants in neuropathic pain in the inhibitory circuit of the central nervous system: GAD65 and KCC2 were increased in the spinal cord of CCI rats after HDAC2 knockdown. Thus, our research confirmed that HDAC2 was involved in mechanical and thermal hyperalgesia induced by peripheral nerve injury. Furthermore, GAD65 and KCC2 were the possible downstream targets of HDAC2 in pain modulation pathways.