Lin Tzer-Bin, Hsieh Ming-Chun, Lai Cheng-Yuan, Cheng Jen-Kun, Wang Hsueh-Hsiao, Chau Yat-Pang, Chen Gin-Den, Peng Hsien-Yu
Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
J Pineal Res. 2016 Apr;60(3):263-76. doi: 10.1111/jpi.12307. Epub 2016 Jan 29.
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, 30 minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3 hr 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.
褪黑素（MLT；N-乙酰-5-甲氧基色胺）在慢性疼痛状态下具有镇痛特性。尽管近年来将MLT与表观遗传机制联系起来的研究呈指数级增长，但很少有研究探讨MLT相关的表观遗传修饰对疼痛状态的影响。在此，我们报告，与行为性痛觉过敏一起，脊神经结扎（SNL）诱导磷酸酶2A（PP2Ac）催化亚基的表达降低，并增强组蛋白脱乙酰酶4（HDAC4）的磷酸化和细胞质积累，这在表观遗传上减轻了HDAC4抑制的hmgb1基因转录，导致大鼠同侧背角中高迁移率族蛋白B1（HMGB1）表达选择性增加。脊髓PP2Ac表达的局部敲低也导致行为性痛觉过敏，其蛋白质表达与SNL观察到的相似。值得注意的是，鞘内注射MLT可增加PP2Ac表达、HDAC4去磷酸化和核积累，恢复HDAC4介导的hmgb1抑制，并减轻SNL致敏的行为性疼痛；这些作用均被脊髓注射4P-PDOT（一种MT2受体拮抗剂，在MLT前30分钟）和冈田酸（OA，一种PP2A抑制剂，在MLT后3小时）所抑制。我们的研究结果证明了一种新的机制，即MLT通过表观遗传修饰改善神经性痛觉过敏。这种MLT表现出的抗痛觉过敏是由MT2增强的PP2Ac表达介导的，该表达将PP2Ac与HDAC4偶联以诱导HDAC4去磷酸化和核输入，从而增加HDAC4与hmgb1基因启动子的结合并上调背角神经元中HMGB1的表达。
