Department of Anesthesiology & Critical Care Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
J Pain. 2024 Feb;25(2):428-450. doi: 10.1016/j.jpain.2023.09.015. Epub 2023 Sep 28.
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 naïve 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 naïve 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 naïve mice. Electrophysiological characterization profile includes a shift where ∼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.
确定和解决慢性神经性疼痛的分子复杂性是一个重大的挑战。在众多组蛋白去乙酰化酶中，I 类（HDAC1-3）和 III 类（sirtuins）在实验性疼痛模型中研究最多，在这些模型中，抑制剂预处理而不是后处理可消除与疼痛相关的行为的发展。在第 3 周进行的较少研究的 IIa 类 HDAC4/5 选择性抑制剂 LMK235 的后期治疗可将两种慢性三叉神经病理性疼痛模型中的三叉神经节 HDAC5 RNA 和蛋白增加降低至模型诱导后第 10 周测量的正常小鼠水平。在下肢炎症性疼痛模型中报告的 HDAC4 RNA 在三叉神经模型中并不明显。在三叉神经节（TG）中，第 10 周持续存在的许多其他基因改变在接受 LMK235 治疗的小鼠中恢复到正常水平。在 LMK235 治疗的小鼠中，重要的与疼痛相关的上调基因 Hoxc8、b9、d8；P2rx4、Cckbr、生长激素（Gh）和 Schlafen（Slfn4）显著减少。在损伤后 Sostdc1、TTr 和 Folr1 等轴突再生/修复基因的倍数增加被 LMK235 治疗增加了一倍。与 vehicle 处理的对照组相比，LMK235 降低了从神经损伤的小鼠中分离的培养的三叉神经节神经元的兴奋性，而对正常小鼠的神经元没有影响。电生理特征分析包括记录到的在 LMK235 处理条件下约 20%的小神经元具有高阈值，而在对照条件下没有神经元具有高阈值的情况发生变化。LMK235 逆转了雄性和雌性慢性三叉神经病理性疼痛模型中的长期机械性和冷敏感性，防止了焦虑和抑郁样行为的发生。观点：这里的数据支持 HDAC5 作为慢性三叉神经病理性疼痛持续存在的关键表观遗传因素，通过研究 RNA 改变、TG 神经元兴奋性和与疼痛相关的行为来验证。在第 3 周给予 HDAC5 抑制剂可在第 10 周恢复 RNA 平衡，而对伤口愈合和慢性炎症的 RNA 的上调反应仍然存在。
