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

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere12436
JournalJournal of Pineal Research
Volume63
Issue number4
DOIs
Publication statusPublished - Nov 1 2017

Fingerprint

Metabotropic Glutamate 5 Receptor
Dioxygenases
Melatonin
Pain
Melatonin MT2 Receptor
Epigenomics
Posterior Horn Cells
Spinal Nerves
Hypersensitivity
Freund's Adjuvant
Hyperalgesia
Ligation
5-Methoxytryptamine
Genes
1-methylcytosine
Spinal Injections
Injections
Neuralgia
Analgesia
Proteins

Keywords

  • demethylation
  • melatonin
  • mGluR5
  • MT2
  • Tet1

ASJC Scopus subject areas

  • Endocrinology

Cite this

Hsieh, M. C., Ho, Y. C., Lai, C. Y., Chou, D., Wang, H. H., Chen, G. D., ... 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

Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain. / Hsieh, Ming Chun; Ho, Yu Cheng; Lai, Cheng Yuan; Chou, Dylan; Wang, Hsueh Hsiao; Chen, Gin Den; Lin, Tzer Bin; Peng, Hsien Yu.

In: Journal of Pineal Research, Vol. 63, No. 4, e12436, 01.11.2017.

Research output: Contribution to journalArticle

Hsieh, MC, Ho, YC, Lai, CY, Chou, D, Wang, HH, Chen, GD, Lin, TB & Peng, HY 2017, 'Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain', Journal of Pineal Research, vol. 63, no. 4, e12436. https://doi.org/10.1111/jpi.12436
Hsieh, Ming Chun ; Ho, Yu Cheng ; Lai, Cheng Yuan ; Chou, Dylan ; Wang, Hsueh Hsiao ; Chen, Gin Den ; Lin, Tzer Bin ; Peng, Hsien Yu. / Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain. In: Journal of Pineal Research. 2017 ; Vol. 63, No. 4.
@article{0519567f0c9e4349a72a4604d2c89b83,
title = "Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain",
abstract = "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 na{\"i}ve 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.",
keywords = "demethylation, melatonin, mGluR5, MT2, Tet1",
author = "Hsieh, {Ming Chun} and Ho, {Yu Cheng} and Lai, {Cheng Yuan} and Dylan Chou and Wang, {Hsueh Hsiao} and Chen, {Gin Den} and Lin, {Tzer Bin} and Peng, {Hsien Yu}",
year = "2017",
month = "11",
day = "1",
doi = "10.1111/jpi.12436",
language = "English",
volume = "63",
journal = "Journal of Pineal Research",
issn = "0742-3098",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Melatonin impedes Tet1-dependent mGluR5 promoter demethylation to relieve pain

AU - Hsieh, Ming Chun

AU - Ho, Yu Cheng

AU - Lai, Cheng Yuan

AU - Chou, Dylan

AU - Wang, Hsueh Hsiao

AU - Chen, Gin Den

AU - Lin, Tzer Bin

AU - Peng, Hsien Yu

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - demethylation

KW - melatonin

KW - mGluR5

KW - MT2

KW - Tet1

UR - http://www.scopus.com/inward/record.url?scp=85031715186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85031715186&partnerID=8YFLogxK

U2 - 10.1111/jpi.12436

DO - 10.1111/jpi.12436

M3 - Article

AN - SCOPUS:85031715186

VL - 63

JO - Journal of Pineal Research

JF - Journal of Pineal Research

SN - 0742-3098

IS - 4

M1 - e12436

ER -