PMID- 37777035 OWN - NLM STAT- MEDLINE DCOM- 20240130 LR - 20240206 IS - 1528-8447 (Electronic) IS - 1526-5900 (Print) IS - 1526-5900 (Linking) VI - 25 IP - 2 DP - 2024 Feb TI - Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice. PG - 428-450 LID - S1526-5900(23)00543-6 [pii] LID - 10.1016/j.jpain.2023.09.015 [doi] AB - Identifying and resolving molecular complexities underlying chronic neuropathic pain is a significant challenge. Among the numerous classes of histone deacetylases, Class I (HDAC 1-3) and Class III (sirtuins) have been best studied in experimental pain models where inhibitor pre-treatments but not post-treatments abrogate the development of pain-related behaviors. Post-treatment here in week 3 with less well-studied Class IIa HDAC4/5 selective inhibitor LMK235 diminishes the trigeminal ganglia increases of HDAC5 RNA and protein in two chronic orofacial neuropathic pain models to levels measured in naive mice at week 10 post-model induction. HDAC4 RNA reported in lower limb inflammatory pain models is not evident in the trigeminal models. Many other gene alterations persisting at week 10 in the trigeminal ganglia (TG) are restored to naive levels in mice treated with LMK235. Important pain-related upregulated genes Hoxc8,b9,d8; P2rx4, Cckbr, growth hormone (Gh), and schlafen (Slfn4) are greatly reduced in LMK235-treated mice. Fold increase in axon regeneration/repair genes Sostdc1, TTr, and Folr1 after injury are doubled by LMK235 treatment. LMK235 reduces the excitability of trigeminal ganglia neurons in culture isolated from nerve injured mice compared to vehicle-treated controls, with no effect on neurons from naive mice. Electrophysiological characterization profile includes a shift where approximately 20% of the small neurons recorded under LMK235-treated conditions are high threshold, whereas none of the neurons under control conditions have high thresholds. LMK235 reverses long-standing mechanical and cold hypersensitivity in chronic trigeminal neuropathic pain models in males and females (5,10 mg/kg), preventing development of anxiety- and depression-like behaviors. PERSPECTIVE: Data here support HDAC5 as key epigenetic factor in chronic trigeminal neuropathic pain persistence, validated with the study of RNA alterations, TG neuronal excitability, and pain-related behaviors. HDAC5 inhibitor given in week 3 restores RNA balance at 10 weeks, while upregulation remains for response to wound healing and chronic inflammation RNAs. CI - Published by Elsevier Inc. FAU - Westlund, Karin N AU - Westlund KN AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Montera, Marena AU - Montera M AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Goins, Aleyah E AU - Goins AE AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Shilling, Mark W AU - Shilling MW AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Afaghpour-Becklund, Mitra AU - Afaghpour-Becklund M AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Alles, Sascha R A AU - Alles SRA AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. FAU - Elise Hui, S AU - Elise Hui S AD - Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico. LA - eng GR - I01 BX002695/BX/BLRD VA/United States GR - R21 DE028096/DE/NIDCR NIH HHS/United States GR - UG3 NS123958/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20230928 PL - United States TA - J Pain JT - The journal of pain JID - 100898657 RN - EC 3.5.1.98 (Histone Deacetylases) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (LMK-235) RN - 0 (Benzamides) SB - IM MH - Animals MH - Male MH - Mice MH - Axons MH - Epigenesis, Genetic MH - Histone Deacetylases/metabolism MH - Nerve Regeneration MH - *Neuralgia/drug therapy MH - Trigeminal Ganglion/metabolism MH - *Histone Deacetylase Inhibitors/administration & dosage MH - *Benzamides/administration & dosage PMC - PMC10842645 MID - NIHMS1935787 OTO - NOTNLM OT - Anxiety OT - Axonal repair genes OT - Chronic pain OT - Patch-clamp OT - Trigeminal ganglia COIS- KNW acknowledges a role as an unpaid consultant with NeuroChronix and USA Elixeria Biotech. All other authors declare no conflicts of interest. This communication does not necessarily reflect views of the Department of Veterans Affairs or the U.S. government. EDAT- 2023/10/01 04:44 MHDA- 2024/01/22 06:42 PMCR- 2025/02/01 CRDT- 2023/09/30 19:15 PHST- 2023/03/22 00:00 [received] PHST- 2023/09/13 00:00 [revised] PHST- 2023/09/21 00:00 [accepted] PHST- 2025/02/01 00:00 [pmc-release] PHST- 2024/01/22 06:42 [medline] PHST- 2023/10/01 04:44 [pubmed] PHST- 2023/09/30 19:15 [entrez] AID - S1526-5900(23)00543-6 [pii] AID - 10.1016/j.jpain.2023.09.015 [doi] PST - ppublish SO - J Pain. 2024 Feb;25(2):428-450. doi: 10.1016/j.jpain.2023.09.015. Epub 2023 Sep 28.