Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model

Robert J. Danaher, Liping Zhang, Connor J. Donley, Nashwin A. Laungani, S. Elise Hui, Craig S. Miller, Karin N. Westlund

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG. Thirty-four genes are significantly (p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.

Original languageEnglish
JournalMolecular Pain
StatePublished - Aug 1 2018

Bibliographical note

Funding Information:
The authors thank Dr. Fei Ma for assistance with the TIC injury model and Joseph B Cardosi, Nathan Messenger, and Guan Hanjun for their assistance with counting of H3K9 and NeuN-positive neurons on TG sections.

Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: These studies were funded by NIH COBRE grant 2P20RR020145 (to RD, CM, and KNW) and VA Merit grant BX002695 (to KNW). This communication does not necessarily reflect the views of the Department of Veterans Affairs or the U.S. government.

Publisher Copyright:
© The Author(s) 2018.


  • H3K9 acetylation
  • HDAC inhibitor
  • Orofacial pain
  • epigenetic regulation
  • gene microarray
  • mechanical allodynia
  • mice
  • trigeminal

ASJC Scopus subject areas

  • Molecular Medicine
  • Cellular and Molecular Neuroscience
  • Anesthesiology and Pain Medicine


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