Epigenetic HDAC5 Inhibitor Reverses Craniofacial Neuropathic Pain in Mice

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 similar to 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 anxietyand 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 painrelated 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. (R) Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).