Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha 410008, Hunan, China.
Neuroscience. 2018 May 1;377:138-149. doi: 10.1016/j.neuroscience.2018.02.026. Epub 2018 Feb 23.
Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of μ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats. TSA application suppressed HDAC2 expression in cultured PC12 cells and reversed the augmented HDAC2 in BCP rats. An RNA-interfering strategy confirmed the essential role of HDAC2 in the modulation of mechanical hyperalgesia following tumor cell inoculation, and we further examined its possible downstream targets. Notably, HDAC2 knock-down did not restore MOR expression, but it robustly reversed the down-regulation of potassium-chloride cotransporter 2 (KCC2). The impaired KCC2 expression is a vital mechanism of many types of pathological pain. Therefore, our results demonstrated that HDAC2 in spinal cord contributed to the mechanical hyperalgesia in BCP rats, and this effect may be associated with KCC2 modulation.
表观遗传调控参与多种病理性疼痛的机制，因此针对相关调节剂可能是治疗疼痛的一种有前途的策略。我们之前的研究通过恢复 μ-阿片受体（MOR）表达，发现组蛋白去乙酰化酶（HDAC）抑制剂 Trichostatin A（TSA）对骨癌痛（BCP）大鼠模型的机械性痛觉过敏具有镇痛作用。然而，参与 BCP 的特定类型的 HDAC 尚未被探索。本研究调查了一些常见的 HDAC 的表达模式，发现 HDAC2 在 BCP 大鼠的脊髓中呈时间依赖性上调。TSA 应用抑制培养的 PC12 细胞中 HDAC2 的表达，并逆转 BCP 大鼠中增强的 HDAC2。RNA 干扰策略证实了 HDAC2 在肿瘤细胞接种后机械性痛觉过敏调节中的重要作用，我们进一步研究了其可能的下游靶点。值得注意的是，HDAC2 敲低并未恢复 MOR 表达，但它强烈逆转了钾氯离子共转运蛋白 2（KCC2）的下调。受损的 KCC2 表达是许多类型病理性疼痛的重要机制。因此，我们的结果表明，脊髓中的 HDAC2 有助于 BCP 大鼠的机械性痛觉过敏，这种作用可能与 KCC2 调节有关。
