title: HDAC4 is required for inflammation-associated thermal hypersensitivity.
abstract: Transcriptional alterations are characteristic of persistent pain states, but the key regulators remain elusive. HDAC4 is a transcriptional corepressor that has been linked to synaptic plasticity and neuronal excitability, mechanisms that may be involved in peripheral and central sensitization. Using a conditional knockout (cKO) strategy in mice, we sought to determine whether the loss of HDAC4 would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely unnecessary for transcriptional regulation of naïve sensory neurons but was essential for appropriate transcriptional responses after injury, with Calca and Trpv1 expression consistently down-regulated in HDAC4 cKO compared to levels in the littermate controls (0.2-0.44-fold change, n = 4 in 2 separate experiments). This down-regulation corresponded to reduced sensitivity to 100 nM capsaicin in vitro (IC50 = 230 ± 20 nM, 76 ± 4.4% wild-type capsaicin responders vs. 56.9 ± 4.7% HDAC4 cKO responders) and to reduced thermal hypersensitivity in the complete Freund's adjuvant (CFA) model of inflammatory pain (1.3-1.4-fold improvement over wild-type controls; n = 5-12, in 2 separate experiments). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors.
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom megan.crow@kcl.ac.uk.
authors.forename: Megan
authors.initials: M
authors.lastname: Crow
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Nikita
authors.initials: N
authors.lastname: Khovanov
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Jayne H
authors.initials: JH
authors.lastname: Kelleher
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Simone
authors.initials: S
authors.lastname: Sharma
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Grant
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Yury
authors.initials: Y
authors.lastname: Bogdanov
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
authors.affiliation: *Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom, UCL Genomics, Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.
authors.forename: Franziska
authors.initials: F
authors.lastname: Denk
mesh_terms: D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005620:Freund's Adjuvant / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D006967:Hypersensitivity / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
chemical_list: C000606590:Calca protein, mouse; D011498:Protein Precursors; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D002116:Calcitonin; D005620:Freund's Adjuvant; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin
keywords: epigenetics; nerve growth factor; pain; transcription