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Melatonin relieves neuropathic allodynia through spinal MT 2‐enhanced PP 2Ac and downstream HDAC 4 shuttling‐dependent epigenetic modification of hmgb1 transcription
Author(s) -
Lin TzerBin,
Hsieh MingChun,
Lai ChengYuan,
Cheng JenKun,
Wang HsuehHsiao,
Chau YatPang,
Chen GinDen,
Peng HsienYu
Publication year - 2016
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12307
Subject(s) - neuropathic pain , allodynia , dephosphorylation , melatonin , histone deacetylase , chemistry , epigenetics , microbiology and biotechnology , nociception , pharmacology , phosphorylation , receptor , histone , biology , endocrinology , hyperalgesia , biochemistry , phosphatase , gene
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 ( PP 2Ac) and enhanced histone deacetylase 4 ( HDAC 4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC 4‐suppressed hmgb1 gene transcription, resulting in increased high‐mobility group protein B1 ( HMGB 1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock‐down of spinal PP 2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with SNL . Notably, intrathecal administration with MLT increased PP 2Ac expression, HDAC 4 dephosphorylation and nuclear accumulation, restored HDAC 4‐mediated hmgb1 suppression and relieved SNL ‐sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P‐ PDOT (a MT 2 receptor antagonist, 30 minutes before MLT ) and okadaic acid ( OA , a PP 2A 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 MT 2‐enhanced PP 2Ac expression that couples PP 2Ac with HDAC 4 to induce HDAC 4 dephosphorylation and nuclear import, herein increases HDAC 4 binding to the promoter of hmgb1 gene and upregulates HMGB 1 expression in dorsal horn neurons.