title: Modulation of Nerve Injury-induced HDAC4 Cytoplasmic Retention Contributes to Neuropathic Pain in Rats.
abstract: BACKGROUND
  The histone deacetylases (HDACs) have been implicated in pain hypersensitivity. This study investigated the potential involvement of an HDAC4-related mechanism in the spinal nerve ligation (SNL)-induced nociceptive hypersensitivity.
  
  
  METHODS
  The left L5 to L6 spinal nerves of 627 adult male Sprague-Dawley rats were surgically ligated. The withdrawal threshold of hind paws and the abundances, cellular location, and interactions of proteins in the dorsal horn were assayed before and after surgery. The 14-3-3β-targeting small-interfering RNA, a serum- and glucocorticoid-inducible kinase 1 (SGK1) antagonist, or an HDAC inhibitor was spinally injected to elucidate the role of 14-3-3β, SGK1, and HDAC4.
  
  
  RESULTS
  Without affecting the HDAC4 level, SNL provoked SGK1 phosphorylation (mean ± SEM from 0.24 ± 0.02 to 0.78 ± 0.06 at day 7, n = 6), HDAC4 phosphorylation (from 0.38 ± 0.03 to 0.72 ± 0.06 at day 7, n = 6), 14-3-3β expression (from 0.53 ± 0.09 to 0.88 ± 0.09 at day 7, n = 6), cytoplasmic HDAC4 retention (from 1.18 ± 0.16 to 1.92 ± 0.11 at day 7, n = 6), and HDAC4-14-3-3β coupling (approximately 2.4-fold) in the ipsilateral dorsal horn in association with behavioral allodynia. Knockdown of spinal 14-3-3β expression prevented the SNL-provoked HDAC4 retention (from 1.89 ± 0.15 to 1.32 ± 0.08 at day 7, n = 6), HDAC4-14-3-3β coupling (approximately 0.6-fold above SNL 7D), and behavioral allodynia (from 0.16 ± 0.3 to 6 ± 1.78 at day 7, n = 7), but not SGK1 (from 0.78 ± 0.06 to 0.71 ± 0.04 at day 7, n = 6) or HDAC4 (from 0.75 ± 0.15 to 0.68 ± 0.11 at day 7, n = 6) phosphorylation.
  
  
  CONCLUSIONS
  Neuropathic pain maintenance involves the spinal SGK1 activation-dependent HDAC4 phosphorylation and its subsequent association with 14-3-3β that promotes cytoplasmic HDAC4 retention in dorsal horn neurons.
authors: From the Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China (T.-B.L.); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China (T.-B.L.); Department of Biotechnology, Asia University, Taichung, Taiwan, Republic of China (T.-B.L.); Department of Medicine, Mackay Medical College, New Taipei, Taiwan, Republic of China (M.-C.H., C.-Y.L., Y.-P.C., H.-Y.P.); Department of Physiology, School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China (M.-C.H.); Department of Veterinary Medicine, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan, Republic of China (C.-Y.L.); Department of Anesthesiology, Mackay Memorial Hospital, New Taipei, Taiwan, Republic of China (J.-K.C.); School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan, Republic of China (T.R.); and Department of Obstetrics and Gynecology, Chung-Shan Medical University Hospital, Chung-Shan Medical University, Taichung, Taiwan, Republic of China (G.-D.C.).
authors: Tzer-Bin
authors: TB
authors: Lin
authors: Ming-Chun
authors: MC
authors: Hsieh
authors: Cheng-Yuan
authors: CY
authors: Lai
authors: Jen-Kun
authors: JK
authors: Cheng
authors: Yat-Pang
authors: YP
authors: Chau
authors: Ting
authors: T
authors: Ruan
authors: Gin-Den
authors: GD
authors: Chen
authors: Hsien-Yu
authors: HY
authors: Peng
mesh_terms: D000818:Animals; D003593:Cytoplasm / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000473:pathology; D020671:Posterior Horn Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000293:injuries* / Q000378:metabolism* / Q000473:pathology
chemical_list: C559944:HDAC4 protein, rat; D006655:Histone Deacetylases