Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
J Pineal Res. 2017 Nov;63(4). doi: 10.1111/jpi.12436. Epub 2017 Aug 16.
Melatonin (N-acetyl-5-methoxytryptamine)/MT2 receptor-dependent epigenetic modification represents a novel pathway in the treatment of neuropathic pain. Because spinal ten-eleven translocation methylcytosine dioxygenase 1 (Tet1)-dependent epigenetic demethylation has recently been linked to pain hypersensitivity, we hypothesized that melatonin/MT2-dependent analgesia involves spinal Tet1-dependent demethylation. Here, we showed that spinal Tet1 gene transfer by intrathecal delivery of Tet1-encoding vectors to naïve rats produced profound and long-lasting nociceptive hypersensitivity. In addition, enhanced Tet1 expression, Tet1-metabotropic glutamate receptor subtype 5 (mGluR5) promoter coupling, demethylation at the mGluR5 promoter, and mGluR5 expression in dorsal horn neurons were observed. Rats subjected to spinal nerve ligation and intraplantar complete Freund's adjuvant injection displayed tactile allodynia and behavioral hyperalgesia associated with similar changes in the dorsal horn. Notably, intrathecal melatonin injection reversed the protein expression, protein-promoter coupling, promoter demethylation, and pain hypersensitivity induced by Tet1 gene transfer, spinal nerve ligation, and intraplantar complete Freund's adjuvant injection. All the effects caused by melatonin were blocked by pretreatment with a MT2 receptor-selective antagonist. In conclusion, melatonin relieves pain by impeding Tet1-dependent demethylation of mGluR5 in dorsal horn neurons through the MT2 receptor. Our findings link melatonin/MT2 signaling to Tet1-dependent epigenetic demethylation of nociceptive genes for the first time and suggest melatonin as a promising therapy for the treatment of pain.
褪黑素（N-乙酰-5-甲氧基色胺）/MT2 受体依赖性表观遗传修饰代表了治疗神经性疼痛的新途径。由于脊髓 ten-eleven 易位甲基胞嘧啶双加氧酶 1（Tet1）依赖性表观遗传去甲基化最近与疼痛敏化有关，我们假设褪黑素/MT2 依赖性镇痛涉及脊髓 Tet1 依赖性去甲基化。在这里，我们通过鞘内递送 Tet1 编码载体向未处理的大鼠脊髓中转移 Tet1 基因，结果显示出明显而持久的痛觉过敏。此外，观察到 Tet1 表达增强、Tet1 代谢型谷氨酸受体亚型 5（mGluR5）启动子偶联、mGluR5 启动子去甲基化以及背角神经元中 mGluR5 表达增加。脊髓神经结扎和足底完全弗氏佐剂注射的大鼠表现出触觉过敏和行为性痛觉过敏，与背角中类似的变化相关。值得注意的是，鞘内褪黑素注射逆转了 Tet1 基因转移、脊髓神经结扎和足底完全弗氏佐剂注射引起的蛋白表达、蛋白启动子偶联、启动子去甲基化和痛觉过敏。褪黑素的所有作用均被 MT2 受体选择性拮抗剂预处理所阻断。总之，褪黑素通过 MT2 受体阻止背角神经元中 mGluR5 的 Tet1 依赖性去甲基化来缓解疼痛。我们的发现首次将褪黑素/MT2 信号与伤害感受基因的 Tet1 依赖性表观遗传去甲基化联系起来，并表明褪黑素作为治疗疼痛的一种有前途的疗法。
