title: Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription.
abstract: 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.
authors.affiliation: 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.|Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Tzer-Bin
authors.initials: TB
authors.lastname: Lin
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Ming-Chun
authors.initials: MC
authors.lastname: Hsieh
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Lai
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.|Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Jen-Kun
authors.initials: JK
authors.lastname: Cheng
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsueh-Hsiao
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Yat-Pang
authors.initials: YP
authors.lastname: Chau
authors.affiliation: Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan.
authors.forename: Gin-Den
authors.initials: GD
authors.lastname: Chen
authors.affiliation: Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
authors.forename: Hsien-Yu
authors.initials: HY
authors.lastname: Peng
mesh_terms: D000818:Animals; D024243:HMGB1 Protein / Q000096:biosynthesis; D006655:Histone Deacetylases / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053517:Matrix Metalloproteinase 15 / Q000378:metabolism*; D008550:Melatonin / Q000494:pharmacology*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2; D053517:Matrix Metalloproteinase 15; C559944:HDAC4 protein, rat; D006655:Histone Deacetylases; D008550:Melatonin
keywords: HDAC4; HMGB1; MT2 receptor; PP2Ac; allodynia; melatonin