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HDAC4 is required for inflammation‐associated thermal hypersensitivity
Author(s) -
Crow Megan,
Khovanov Nikita,
Kelleher Jayne H.,
Sharma Simone,
Grant Andrew D.,
Bogdanov Yury,
Wood John N.,
McMahon Stephen B.,
Denk Franziska
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-264440
Subject(s) - hdac4 , sensitization , trpv1 , inflammation , nociception , conditional gene knockout , capsaicin , knockout mouse , nociceptor , medicine , phenotype , biology , immunology , neuroscience , microbiology and biotechnology , transient receptor potential channel , receptor , histone , genetics , histone deacetylase , gene
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 Trpvl 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 (IC 50 = 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.—Crow, M., Khovanov, N., Kelleher, J. H., Sharma, S., Grant, A. D., Bogdanov, Y., Wood, J. N., McMahon, S. B., Denk, F. HDAC4 is required for inflammation‐associated thermal hypersensitivity. FASEB J. 29, 3370‐3378 (2015). www.fasebj.org