title: HDAC and HAT inhibitors differently affect analgesia mediated by group II metabotropic glutamate receptors.
abstract: BACKGROUND
  Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key players in epigenetic regulation of gene expression. Analgesic activity by HDAC inhibitors has been reported in different pain models including inflammatory and neuropathic pain. These drugs interfere with gene expression through different mechanisms including chromatin remodeling and/or activation of transcription factors. Among other targets, HDAC inhibitors regulate metabotropic glutamate receptors type 2 (mGlu2) expression in central and peripheral central nervous system. However whether inhibition of HAT activity also regulates mGlu2 expression has not been reported.
  
  
  RESULTS
  Here we report that curcumin (CUR), a naturally occurring compound endowed with p300/CREB-binding protein HAT inhibitory activity, is able to induce a drastic down-regulation of the mGlu2 receptor in the mouse spinal cord after systemic administration together with a marked hypoacetylation of histones H3 and H4 in dorsal root ganglia (DRG). Furthermore, the analgesic activity of the mGlu2/3 agonist, LY379268 is lost after a 3-day treatment with CUR. Conversely the analgesic activity of LY379268 is potentiated in mice pretreated for 5 consecutive days with the HDAC inhibitor, Suberoylanilide Hydroxamic Acid (SAHA), known to induce mGlu2-upregulation.
  
  
  CONCLUSIONS
  Our results demonstrate that systemically injected CUR is able to inhibit H3 and H4 acetylation in the DRG and to down-regulate mGlu2 receptors in the spinal cord. We also demonstrate that long term modification of the mGlu2 expression affects the analgesic properties of the orthosteric mGlu2/3 agonist, LY379268. These data open up the possibility that epigenetic modulators might be given in combination with "traditional" drugs in a context of a multi target approach for a better analgesic efficacy.
authors.forename: Magda
authors.initials: M
authors.lastname: Zammataro
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Sortino
authors.forename: Carmela
authors.initials: C
authors.lastname: Parenti
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
authors.affiliation: Department of Drug Sciences, Section of Pharmacology and Toxicology, University of Catania, 95125 Catania, Italy. chiechio@unict.it.
authors.forename: Santina
authors.initials: S
authors.lastname: Chiechio
mesh_terms: D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018690:Excitatory Amino Acid Agonists; D056572:Histone Deacetylase Inhibitors; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D051548:Histone Acetyltransferases; D003474:Curcumin