Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription
Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription
复制标题
DOI：
10.1111/jpi.12307
复制
发表时间：
2016-04-01
影响因子：
10.3
通讯作者：
Peng, Hsien-Yu
中科院分区：
文献类型：
--
作者：
Lin, Tzer-Bin;Hsieh, Ming-Chun;Peng, Hsien-Yu
褪黑激素（MLT; N-乙酰基-5-甲氧基色胺）在慢性疼痛条件下表现出镇痛特性。虽然近年来将MLT与表观遗传机制联系起来的研究呈指数级增长，但很少有研究调查MLT相关的表观遗传修饰对疼痛状态的贡献。在这里，我们报告说，与行为异常性疼痛一起，脊神经结扎（SNL）诱导磷酸酶2A催化亚基（PP 2Ac）表达减少，并增强组蛋白脱乙酰酶4（HDAC 4）磷酸化和细胞质积聚，这在表观遗传学上减轻了HDAC 4抑制的hmgb 1基因转录，导致高迁移率族蛋白B1（HMGB 1）选择性地在大鼠同侧背角中表达增加。脊髓PP 2Ac表达的局灶性敲低也导致与SNL观察到的类似蛋白表达相关的行为异常性疼痛。值得注意的是，鞘内注射MLT增加了PP 2Ac表达，HDAC 4去磷酸化和核积聚，恢复了HDAC 4介导的hmgb 1抑制，减轻了SNL致敏的行为疼痛;这些作用都被脊髓注射4P-PDOT（MT 2受体拮抗剂，MLT前30分钟）和冈田酸（OA，PP 2A抑制剂，MLT后3小时）抑制。我们的研究结果表明，MLT通过表观遗传修饰改善神经性异常性疼痛的新机制。这种MLT表现出的抗异常性疼痛是由MT 2增强的PP 2Ac表达介导的，其将PP 2Ac与HDAC 4偶联以诱导HDAC 4去磷酸化和核输入，在此增加HDAC 4与hmgb 1基因启动子的结合并上调背角神经元中的HMGB 1表达。
Melatonin (MLT; N-acetyl-5-methoxytryptamine) exhibits analgesic properties in chronic pain conditions. While researches linking MLT to epigenetic mechanisms have grown exponentially over recent years, very few studies have investigated the contribution of MLT-associated epigenetic modification to pain states. Here, we report that together with behavioral allodynia, spinal nerve ligation (SNL) induced a decrease in the expression of catalytic subunit of phosphatase 2A (PP2Ac) and enhanced histone deacetylase 4 (HDAC4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC4-suppressed hmgb1 gene transcription, resulting in increased high-mobility group protein B1 (HMGB1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock-down of spinal PP2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with SNL. Notably, intrathecal administration with MLT increased PP2Ac expression, HDAC4 dephosphorylation and nuclear accumulation, restored HDAC4-mediated hmgb1 suppression and relieved SNL-sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P-PDOT (a MT2 receptor antagonist, 30minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3hr after MLT). Our findings demonstrate a novel mechanism by which MLT ameliorates neuropathic allodynia via epigenetic modification. This MLT-exhibited anti-allodynia is mediated by MT2-enhanced PP2Ac expression that couples PP2Ac with HDAC4 to induce HDAC4 dephosphorylation and nuclear import, herein increases HDAC4 binding to the promoter of hmgb1 gene and upregulates HMGB1 expression in dorsal horn neurons.