Cellular mechanisms of antidepressant drug actions in neuropathic pain models

项目总结 神经性疼痛是一种以感觉、认知和情感症状为特征的慢性疾病。多数 大多数用于治疗这种疾病的药物显示出低疗效和主要副作用。了解 调控外周血细胞传递和维持的表观遗传和转录机制 神经损伤(PNI)症状将是发展新的治疗方法的重要一步。 我们早期的发现确认了表观遗传修饰物组蛋白脱乙酰基酶5(HDAC5)在 神经病理性疼痛模型中抗抑郁药的作用起效和疗效。核中的HDAC5 伏隔(NAC)与染色质复合体结合以抑制几个影响基因的表达 突触功能，包括转录因子MEF2C。父R01提案调查 HDAC5及其下游靶点调节NAC中抗抑郁药作用的机制。 这项补充计划旨在阐明特定细胞类型的表观遗传和转录机制。 在神经病理性疼痛模型中介导单胺靶向抗抑郁药的抗痛觉过敏作用。 单核RNAseq数据的生物信息学分析将补充HDAC5和MEF2C的研究结果 并将提供对与抗抑郁疗效相关的转录事件的洞察。我们 将使用荧光原位杂交、免疫荧光以及免疫印迹来验证关键发现 印迹分析。药理学和遗传学模型将用于测试选定的基因/细胞内途径。 了解单胺类抗抑郁药作用的分子机制 将有助于开发治疗神经病理性疼痛的新的、更有效的药物。

PROJECT SUMMARY Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the drugs used to treat this disorder demonstrate low efficacy and major side-effects. Understanding the epigenetic and transcriptional mechanisms that modulate the transmission and maintenance of peripheral nerve injury (PNI) symptoms will be a major step towards the development of novel treatment approaches. Our earlier findings identified a key role of the epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of antidepressants in models of neuropathic pain. HDAC5 in the Nucleus Accumbens (NAc) binds to chromatin complexes to suppress the expression of several genes that affect synaptic function, including the transcription factor MEF2C. The parent R01 proposal investigates the mechanism by which HDAC5 and downstream targets modulate the actions of antidepressants in the NAc. This supplement project aims to elucidate cell type-specific epigenetic and transcriptomic mechanisms mediating the antiallodynic effects of monoamine-targeting antidepressants in models of neuropathic pain. Bioinformatic analysis of single nuclei RNASeq data will complement findings on HDAC5 and MEF2C actions and will also provide insight on transcriptomic events associated with antidepressant efficacy. We will validate key findings using fluorescent in situ hybridization, immunofluorescence, as well as western blot analysis. Pharmacological and genetic models will be use to test selected genes/intracellular pathways. Understanding the molecular mechanisms mediating the actions of monoamine-targeting antidepressants will help the development of novel and more efficacious medications for the treatment of neuropathic pain.