Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain

Ming Chun Hsieh, Yu Cheng Ho, Cheng Yuan Lai, Dylan Chou, Hsueh Hsiao Wang, Gin Den Chen, Tzer Bin Lin, Hsien Yu Peng

研究成果: 雜誌貢獻文章

12 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
文章編號e12436
期刊Journal of Pineal Research
63
發行號4
DOIs
出版狀態已發佈 - 十一月 1 2017

ASJC Scopus subject areas

  • Endocrinology

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    Hsieh, M. C., Ho, Y. C., Lai, C. Y., Chou, D., Wang, H. H., Chen, G. D., Lin, T. B., & Peng, H. Y. (2017). Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain. Journal of Pineal Research, 63(4), [e12436]. https://doi.org/10.1111/jpi.12436