title: Inhibition of class II histone deacetylases in the spinal cord attenuates inflammatory hyperalgesia.
abstract: BACKGROUND
  Several classes of histone deacetylases (HDACs) are expressed in the spinal cord that is a critical structure of the nociceptive pathway. HDAC-regulated histone acetylation is an important component of chromatin remodeling leading to epigenetic regulation of gene transcription. To understand the role of histone acetylation in epigenetic regulation of pathological pain, we have studied the impact of different classes of HDACs in the spinal cord on inflammatory hyperalgesia induced by complete Freund's adjuvant (CFA).
  
  
  RESULTS
  We intrathecally applied inhibitors specific to different classes of HDACs and evaluated their impact on inflammatory hyperalgesia. Pre-injected inhibitors targeting class I as well as II (SAHA, TSA, LAQ824) or IIa (VPA, 4-PB) HDACs significantly delayed the thermal hyperalgesia induced by unilateral CFA injection in the hindpaw. Existing hyperalgesia induced by CFA was also attenuated by the HDAC inhibitors (HDACIs). In contrast, these inhibitors did not interfere with the thermal response either in naïve animals, or on the contralateral side of inflamed animals. Interestingly, MS-275 that specifically inhibits class I HDACs failed to alter the hyperalgesia although it increased histone 3 acetylation in the spinal cord as SAHA did. Using immunoblot analysis, we further found that the levels of class IIa HDAC members (HDAC4, 5, 7, 9) in the spinal dorsal horn were upregulated following CFA injection while those of class I HDAC members (HDAC1, 2, 3) remained stable or were slightly reduced.
  
  
  CONCLUSIONS
  Our data suggest that activity of class II HDACs in the spinal cord is critical to the induction and maintenance of inflammatory hyperalgesia induced by CFA, while activity of class I HDACs may be unnecessary. Comparison of the effects of HDACIs specific to class II and IIa as well as the expression pattern of different HDACs in the spinal cord in response to CFA suggests that the members of class IIa HDACs may be potential targets for attenuating persistent inflammatory pain.
authors.affiliation: Department of Neural and Pain Sciences, University of Maryland, Baltimore, Maryland 21117, USA. gbai@umaryland.edu
authors.forename: Guang
authors.initials: G
authors.lastname: Bai
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.forename: Shiping
authors.initials: S
authors.lastname: Zou
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Ronald
authors.initials: R
authors.lastname: Dubner
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D005620:Freund's Adjuvant; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006655:Histone Deacetylases / Q000378:metabolism*; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy*; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D013696:Temperature; D013997:Time Factors
chemical_list: D056572:Histone Deacetylase Inhibitors; D005620:Freund's Adjuvant; D006655:Histone Deacetylases
references.citation: Cancer Lett. 2009 Aug 8;280(2):211-21
references.pmid: 19289255
references.citation: Mol Cancer Res. 2007 Oct;5(10):981-9
references.pmid: 17951399
references.citation: Epigenetics. 2008 Jan-Feb;3(1):28-37
references.pmid: 18326939
references.citation: CNS Drug Rev. 2003 Summer;9(2):199-216
references.pmid: 12847559
references.citation: Cell. 2007 Feb 23;128(4):693-705
references.pmid: 17320507
references.citation: Pain. 1992 Oct;51(1):5-17
references.pmid: 1454405
references.citation: Pediatrics. 2004 Apr;113(4 Suppl):1076-83
references.pmid: 15060202
references.citation: J Biol Chem. 2002 Feb 22;277(8):6656-66
references.pmid: 11739383
references.citation: Mol Neurobiol. 2009 Aug;40(1):33-45
references.pmid: 19396637
references.citation: Mol Pain. 2010 Jul 23;6:44
references.pmid: 20653959
references.citation: J Neurophysiol. 1996 Nov;76(5):3025-37
references.pmid: 8930252
references.citation: J Neurochem. 2006 Jul;98(1):193-202
references.pmid: 16805808
references.citation: J Neurosci. 2010 Jun 23;30(25):8624-36
references.pmid: 20573908
references.citation: Nature. 2001 Oct 18;413(6857):739-43
references.pmid: 11607033
references.citation: BMC Cancer. 2008 Aug 19;8:243
references.pmid: 18713462
references.citation: Cancer. 2007 Sep 1;110(5):943-54
references.pmid: 17647267
references.citation: J Neurosci. 2010 Mar 31;30(13):4806-14
references.pmid: 20357131
references.citation: Eur J Neurosci. 2004 Jun;19(12):3375-81
references.pmid: 15217394
references.citation: J Neurochem. 2006 Oct;99(2):371-80
references.pmid: 17029593
references.citation: Brief Funct Genomic Proteomic. 2006 Sep;5(3):190-208
references.pmid: 16980317
references.citation: Anticancer Drugs. 2007 Apr;18(4):363-70
references.pmid: 17351388
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15179-84
references.pmid: 11742087
references.citation: J Clin Endocrinol Metab. 2005 Aug;90(8):4936-45
references.pmid: 15899953
references.citation: Mol Pharmacol. 2005 Jun;67(6):2032-9
references.pmid: 15769948
references.citation: Mol Pain. 2007 Oct 31;3:32
references.pmid: 17974009
references.citation: Pain. 2004 Aug;110(3):588-596
references.pmid: 15288399
references.citation: J Cell Sci. 2003 Jun 1;116(Pt 11):2117-24
references.pmid: 12730288
references.citation: J Clin Oncol. 2005 Jun 10;23(17):3971-93
references.pmid: 15897549
references.citation: Hum Mol Genet. 2004 Jun 1;13(11):1183-92
references.pmid: 15102712
references.citation: Trends Genet. 2007 Dec;23(12):605-13
references.pmid: 18023497
references.citation: Curr Opin Immunol. 2007 Dec;19(6):694-700
references.pmid: 17720468
references.citation: Learn Mem. 2007 Apr 06;14(4):268-76
references.pmid: 17522015
references.citation: Drug Metab Dispos. 2006 Apr;34(4):612-20
references.pmid: 16415118
references.citation: J Clin Invest. 2005 Nov;115(11):3104-16
references.pmid: 16224541
references.citation: J Neurosci. 2009 Sep 16;29(37):11451-60
references.pmid: 19759294
references.citation: Pain. 1988 Dec;35(3):313-326
references.pmid: 2906426
references.citation: J Neurochem. 2003 Aug;86(4):992-1005
references.pmid: 12887696
references.citation: J Physiol. 2002 Apr 15;540(Pt 2):593-606
references.pmid: 11956346
references.citation: Science. 2009 Aug 14;325(5942):834-40
references.pmid: 19608861
references.citation: J Neurosci. 2008 Nov 12;28(46):11753-9
references.pmid: 19005036
references.citation: J Neurosci. 2001 Mar 1;21(5):1590-9
references.pmid: 11222649
references.citation: J Neurosci. 2004 Feb 18;24(7):1637-45
references.pmid: 14973242
references.citation: J Neurosci. 1998 Jul 15;18(14):5456-62
references.pmid: 9651226
references.citation: Mol Pharmacol. 2009 May;75(5):1014-20
references.pmid: 19255242
references.citation: Bioessays. 2003 Oct;25(10):930-9
references.pmid: 14505360
references.citation: Br J Pharmacol. 2005 Sep;146(2):198-208
references.pmid: 15997234
references.citation: Onkologie. 2008 Nov;31(11):629-33
references.pmid: 19145098
references.citation: Mol Cancer Ther. 2009 Jun;8(6):1409-20
references.pmid: 19509247
references.citation: J Neurosci. 2002 Oct 1;22(19):8422-8
references.pmid: 12351716
references.citation: Am J Physiol Gastrointest Liver Physiol. 2002 Feb;282(2):G307-16
references.pmid: 11804852
references.citation: J Neurosci. 1992 Sep;12(9):3671-5
references.pmid: 1326611
references.citation: Biochem J. 2008 Jan 15;409(2):581-9
references.pmid: 17868033
references.citation: Nature. 2007 May 24;447(7143):418-24
references.pmid: 17522675
references.citation: EMBO J. 2001 Dec 17;20(24):6969-78
references.pmid: 11742974
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1587-92
references.pmid: 16432198
references.citation: Prog Neurobiol. 2002 Apr;66(5):285-306
references.pmid: 12015197
references.citation: Mol Pharmacol. 2010 Jul;78(1):58-68
references.pmid: 20385708
references.citation: J Neurosci. 2007 Aug 8;27(32):8699-708
references.pmid: 17687047
references.citation: Neuron. 2007 Nov 8;56(3):517-29
references.pmid: 17988634
references.citation: Science. 2010 Feb 19;327(5968):1000-4
references.pmid: 20167786
references.citation: Cell. 2002 Jan 11;108(1):31-43
references.pmid: 11792319
references.citation: Nat Rev Genet. 2009 Jan;10(1):32-42
references.pmid: 19065135
references.citation: Mol Cell Biol. 2001 Sep;21(18):6312-21
references.pmid: 11509672
references.citation: Physiol Behav. 1986;37(5):827-31
references.pmid: 3022319
references.citation: Nat Rev Neurosci. 2006 Oct;7(10):784-96
references.pmid: 16988654
references.citation: J Neurosci. 2007 Jun 6;27(23):6163-73
references.pmid: 17553988
references.citation: PLoS One. 2009 Aug 12;4(8):e6612
references.pmid: 19672313
references.citation: Pain. 2007 Sep;131(1-2):3.e1-4
references.pmid: 17574758
references.citation: Nature. 2007 May 24;447(7143):433-40
references.pmid: 17522677
references.citation: Nat Neurosci. 2006 Apr;9(4):519-25
references.pmid: 16501568
references.citation: Science. 2010 Feb 19;327(5968):1004-7
references.pmid: 20167787
references.citation: Neurotherapeutics. 2007 Jan;4(1):130-7
references.pmid: 17199028
references.citation: Oncologist. 2004;9(5):571-91
references.pmid: 15477643
references.citation: FASEB J. 2008 Oct;22(10):3432-42
references.pmid: 18559989
references.citation: Cancer Lett. 2009 Feb 18;274(2):169-76
references.pmid: 18635312
references.citation: J Mol Neurosci. 2007;31(1):47-58
references.pmid: 17416969
references.citation: Rheumatology (Oxford). 2006 May;45(5):589-94
references.pmid: 16332950
references.citation: Mol Cell Biol. 2005 Apr;25(8):2873-84
references.pmid: 15798178
references.citation: Development. 2004 Jun;131(12):2983-95
references.pmid: 15169759
references.citation: Physiol Behav. 2003 Mar;78(3):375-83
references.pmid: 12676272
references.citation: Curr Pharm Des. 2008;14(6):505-28
references.pmid: 18336297
references.citation: Cancer Lett. 2009 Aug 8;280(2):154-9
references.pmid: 19101082