title: HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain.
abstract: Histone deacetylase inhibitors (HDACIs) interfere with the epigenetic process of histone acetylation and are known to have analgesic properties in models of chronic inflammatory pain. The aim of this study was to determine whether these compounds could also affect neuropathic pain. Different class I HDACIs were delivered intrathecally into rat spinal cord in models of traumatic nerve injury and antiretroviral drug-induced peripheral neuropathy (stavudine, d4T). Mechanical and thermal hypersensitivity was attenuated by 40% to 50% as a result of HDACI treatment, but only if started before any insult. The drugs globally increased histone acetylation in the spinal cord, but appeared to have no measurable effects in relevant dorsal root ganglia in this treatment paradigm, suggesting that any potential mechanism should be sought in the central nervous system. Microarray analysis of dorsal cord RNA revealed the signature of the specific compound used (MS-275) and suggested that its main effect was mediated through HDAC1. Taken together, these data support a role for histone acetylation in the emergence of neuropathic pain.
authors.affiliation: King's College London, Wolfson Centre for Age-Related Diseases, London SE1 1UL, United Kingdom Pain Research Group, Department of Surgery and Cancer, Imperial College London, London SW10 9NH, United Kingdom Neusentis, Pfizer Worldwide R&D, Cambridge CB21 6GS, United Kingdom King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, London SE5 9NU, United Kingdom UCL Genomics, UCL Cancer Institute and Wolfson Institute for Biomedical Research, London WC1E 6BT, United Kingdom Computational Sciences Center of Emphasis, Pfizer Worldwide Research and Development, Cambridge, MA, United States.
authors.forename: Franziska
authors.initials: F
authors.lastname: Denk
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Ben
authors.initials: B
authors.lastname: Sidders
authors.forename: Angela
authors.initials: A
authors.lastname: Bithell
authors.forename: Megan
authors.initials: M
authors.lastname: Crow
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.forename: Simone
authors.initials: S
authors.lastname: Sharma
authors.forename: Daniel
authors.initials: D
authors.lastname: Ziemek
authors.forename: Andrew S C
authors.initials: ASC
authors.lastname: Rice
authors.forename: Noel J
authors.initials: NJ
authors.lastname: Buckley
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000009:adverse effects; D001549:Benzamides / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000150:complications*; D010147:Pain Measurement; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D044966:Anti-Retroviral Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C118739:entinostat; C523184:mocetinostat
keywords: Histone deacetylase; Histone deacetylase inhibitors; Neuropathic pain