PMID- 30178698 OWN - NLM STAT- MEDLINE DCOM- 20190114 LR - 20190114 IS - 1744-8069 (Electronic) IS - 1744-8069 (Linking) VI - 14 DP - 2018 Jan-Dec TI - Histone deacetylase inhibitors prevent persistent hypersensitivity in an orofacial neuropathic pain model. PG - 1744806918796763 LID - 10.1177/1744806918796763 [doi] LID - 1744806918796763 AB - 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. FAU - Danaher, Robert J AU - Danaher RJ AD - 1 Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA. FAU - Zhang, Liping AU - Zhang L AD - 1 Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA. AD - 2 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA. FAU - Donley, Connor J AU - Donley CJ AD - 2 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA. FAU - Laungani, Nashwin A AU - Laungani NA AD - 1 Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA. FAU - Hui, S Elise AU - Hui SE AD - 3 Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Science Center, Albuquerque, NM, USA. FAU - Miller, Craig S AU - Miller CS AD - 1 Department of Oral Health Practice, College of Dentistry, University of Kentucky, Lexington, KY, USA. FAU - Westlund, Karin N AU - Westlund KN AD - 2 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA. AD - 3 Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Science Center, Albuquerque, NM, USA. LA - eng GR - I01 BX002695/BX/BLRD VA/United States GR - P20 RR020145/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Mol Pain JT - Molecular pain JID - 101242662 RN - 0 (Activating Transcription Factor 3) RN - 0 (Atf3 protein, mouse) RN - 0 (Benzamides) RN - 0 (Cornified Envelope Proline-Rich Proteins) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Nerve Tissue Proteins) RN - 0 (Nylons) RN - 0 (Pyridines) RN - 0 (Pyrroles) RN - 0 (SAHA-PIP-delta) RN - 0 (Sprr1a protein, mouse) RN - 1ZNY4FKK9H (entinostat) RN - EC 3.5.1.98 (Histone Deacetylases) SB - IM MH - Activating Transcription Factor 3/genetics/metabolism MH - Animals MH - Benzamides/therapeutic use MH - Cornified Envelope Proline-Rich Proteins/genetics/metabolism MH - Disease Models, Animal MH - Facial Pain/*complications/etiology/pathology MH - Functional Laterality MH - Ganglia, Spinal/pathology MH - Gene Expression Regulation/drug effects/*physiology MH - Histone Deacetylase Inhibitors/*therapeutic use MH - Histone Deacetylases/metabolism MH - Hyperalgesia/*etiology/*prevention & control MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Nerve Tissue Proteins/genetics/metabolism MH - Nylons MH - Pain Threshold/drug effects MH - Physical Stimulation/adverse effects MH - Pyridines/therapeutic use MH - Pyrroles/therapeutic use MH - Trigeminal Nerve Injuries/complications MH - Vibrissae/innervation PMC - PMC6124181 OTO - NOTNLM OT - H3K9 acetylation OT - HDAC inhibitor OT - Orofacial pain OT - epigenetic regulation OT - gene microarray OT - mechanical allodynia OT - mice OT - trigeminal EDAT- 2018/09/05 06:00 MHDA- 2019/01/15 06:00 PMCR- 2018/09/04 CRDT- 2018/09/05 06:00 PHST- 2018/09/05 06:00 [entrez] PHST- 2018/09/05 06:00 [pubmed] PHST- 2019/01/15 06:00 [medline] PHST- 2018/09/04 00:00 [pmc-release] AID - 10.1177_1744806918796763 [pii] AID - 10.1177/1744806918796763 [doi] PST - ppublish SO - Mol Pain. 2018 Jan-Dec;14:1744806918796763. doi: 10.1177/1744806918796763.