PMID- 26732138
OWN - NLM
STAT- MEDLINE
DCOM- 20161213
LR  - 20161230
IS  - 1600-079X (Electronic)
IS  - 0742-3098 (Linking)
VI  - 60
IP  - 3
DP  - 2016 Apr
TI  - Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and 
      downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 
      transcription.
PG  - 263-76
LID - 10.1111/jpi.12307 [doi]
AB  - 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.
CI  - (c) 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Lin, Tzer-Bin
AU  - Lin TB
AD  - Department of Physiology, School of Medicine, College of Medicine, Taipei Medical 
      University, Taipei, Taiwan.
AD  - Graduate Institute of Basic Medical Science, College of Medicine, China Medical 
      University, Taichung, Taiwan.
AD  - Department of Biotechnology, Asia University, Taichung, Taiwan.
FAU - Hsieh, Ming-Chun
AU  - Hsieh MC
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
AD  - Department of Physiology, College of Medicine, National Taiwan University, 
      Taipei, Taiwan.
FAU - Lai, Cheng-Yuan
AU  - Lai CY
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
AD  - Department of Veterinary Medicine, College of Veterinary Medicine, National 
      Chung-Hsing University, Taichung, Taiwan.
FAU - Cheng, Jen-Kun
AU  - Cheng JK
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
AD  - Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
FAU - Wang, Hsueh-Hsiao
AU  - Wang HH
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
FAU - Chau, Yat-Pang
AU  - Chau YP
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
FAU - Chen, Gin-Den
AU  - Chen GD
AD  - Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, 
      Chung-Shan Medical University, Taichung, Taiwan.
FAU - Peng, Hsien-Yu
AU  - Peng HY
AD  - Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20160129
PL  - England
TA  - J Pineal Res
JT  - Journal of pineal research
JID - 8504412
RN  - 0 (HMGB1 Protein)
RN  - 0 (Hbp1 protein, rat)
RN  - EC 3.1.3.16 (Ppp2ca protein, rat)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
RN  - EC 3.4.24.- (Matrix Metalloproteinase 15)
RN  - EC 3.5.1.98 (HDAC4 protein, rat)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - HMGB1 Protein/biosynthesis
MH  - Histone Deacetylases/*metabolism
MH  - Hyperalgesia/*metabolism/pathology
MH  - Male
MH  - Matrix Metalloproteinase 15/*metabolism
MH  - Melatonin/*pharmacology
MH  - Protein Phosphatase 2/*metabolism
MH  - Rats
MH  - Spinal Cord Dorsal Horn/*metabolism/pathology
MH  - Transcription, Genetic/*drug effects
OTO - NOTNLM
OT  - HDAC4
OT  - HMGB1
OT  - MT2 receptor
OT  - PP2Ac
OT  - allodynia
OT  - melatonin
EDAT- 2016/01/07 06:00
MHDA- 2016/12/15 06:00
CRDT- 2016/01/07 06:00
PHST- 2015/12/08 00:00 [received]
PHST- 2016/01/04 00:00 [accepted]
PHST- 2016/01/07 06:00 [entrez]
PHST- 2016/01/07 06:00 [pubmed]
PHST- 2016/12/15 06:00 [medline]
AID - 10.1111/jpi.12307 [doi]
PST - ppublish
SO  - J Pineal Res. 2016 Apr;60(3):263-76. doi: 10.1111/jpi.12307. Epub 2016 Jan 29.