Cellular mechanisms of antidepressant drug actions in neuropathic pain models

神经病理性疼痛模型中抗抑郁药物作用的细胞机制

• 批准号: 10542571
• 负责人: Venetia Zachariou
• 金额: $ 12.05万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10542571
• 关键词: Adverse effects; Affect; Affective; Affective Symptoms; Analgesics; Antidepressive Agents; Attenuated; Bacterial Artificial Chromosomes; Behavioral Assay; Binding; Biochemical; Biological Assay; Brain; Chromatin; Chronic; Chronic Disease; Cognition; Complex; Conflict (Psychology); Development; Disease; Drug usage; Epigenetic Process; Evaluation; Event; Excision; Female; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic approach; HDAC5 gene; Hypersensitivity; Intervention; Knock-out; Lead; Maintenance; Mechanics; Mediating; Modeling; Molecular; Monitor; Motivation; Mus; Neurobehavioral Manifestations; Neurons; Norepinephrine; Nuclear; Nucleus Accumbens; Opioid; Paclitaxel; Pain; Pathway interactions; Peripheral nerve injury; Pharmaceutical Preparations; Population; Property; Recovery; Rewards; Role; Running; Sensory; Serotonin; Social Interaction; Symptoms; Synapses; Testing; Time; Tissues; Tricyclic Antidepressive Agents; Viral Vector; Work; addiction; adeno-associated viral vector; brain circuitry; chemotherapy; chromatin modification; chronic neuropathic pain; chronic pain; chronic pain management; design; drug action; experimental study; inhibitor; insight; knock-down; mechanical allodynia; men' s group; monoamine; mouse model; nerve injury; neural circuit; novel; novel therapeutics; overexpression; pain model; pain relief; painful neuropathy; response; reuptake; reward processing; side effect; small hairpin RNA; spared nerve; synaptic function; transcription factor; transcriptome sequencing

This project aims to elucidate epigenetic and transcriptional mechanisms in the reward brain circuitry which mediate long-term pain states and responses to antidepressant medications. Neuropathic pain is a chronic condition characterized by sensory, cognitive and affective symptoms. Most of the drugs used to treat the pain-like symptoms of this disorder demonstrate low efficacy and major side-effects. And, well documented among classes of opioids many of the current treatments can lead to debilitating addiction. There is a pressing need for the development of more efficacious and better tolerated medications for chronic neuropathic pain. Tricyclic antidepressants (TCAs) and the selective, serotonin/norepinephrine reuptake inhibitors (SNRIs) contain both antiallodynic and antidepressant properties; however, they demonstrate slow onset of action and longtime usage often is accompanied by severe adverse effects. Understanding the intracellular mechanisms mediating the actions of TCAs and SNRIs will help the development of novel and more efficacious medications for the treatment of neuropathic pain. Our earlier findings identified a key role of the epigenetic modifier Histone deacetylase 5 (HDAC5) in the onset of action and efficacy of TCAs/SNRIs 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. Our recent preliminary findings suggest that promotion of MEF2C activity in the NAc leads to recovery from neuropathic pain states. Moving forward, we propose to use genetic mouse models, biochemical and genomic approaches to understand the impact of chronic pain in the nuclear activity of HDAC5, and the NAc circuits associated with HDAC5 actions. Furthermore, we will test known HDAC5 target genes, such as MEF2C, for their ability to promote recovery from chronic pain states and enhance the efficacy of antidepressants. We will employ genomic approaches to identify additional HDAC5 targets and test for their role in chronic pain and SNRI efficacy. Our findings will help to provide insights regarding epigenetic and transcriptional mechanisms that control the maintenance of chronic pain and responsiveness to pain-alleviating drugs.

该项目旨在阐明奖励脑回路中的表观遗传和转录机制， 介导长期疼痛状态和抗抑郁药物的反应。 神经病理性疼痛是一种以感觉、认知和情感症状为特征的慢性疾病。大部分 用于治疗这种疾病的疼痛样症状的药物表现出低的功效和主要的副作用。而且， 在阿片类药物的种类中，有充分的证据表明，目前的许多治疗方法可能导致使人衰弱的成瘾。 目前迫切需要开发更有效和更好耐受的治疗慢性炎症的药物。 神经性疼痛三环类抗抑郁药（TCAs）与选择性5-羟色胺/去甲肾上腺素再摄取 抑制剂（SNRIs）含有抗异常性疼痛和抗抑郁特性;然而，它们表现出缓慢的 起效和长期使用往往伴随着严重的副作用。了解 细胞内机制介导的行动，TCA和SNRIs将有助于发展新的和更多的 用于治疗神经性疼痛的有效药物。我们早期的发现确定了一个关键作用， 表观遗传修饰剂组蛋白脱乙酰酶5（HDAC 5）在TCA/SNRI模型中的起效和疗效 神经性疼痛伏隔核（NAc）中的HDAC 5与染色质复合物结合，以抑制 影响突触功能的几个基因的表达，包括转录因子MEF 2C。我们最近 初步研究结果表明，NAc中MEF 2C活性的促进导致神经病理性疼痛的恢复 states.展望未来，我们建议使用遗传小鼠模型，生物化学和基因组方法， 了解慢性疼痛对HDAC 5核活性的影响，以及与之相关的NAc回路。 HDAC 5操作。此外，我们将测试已知的HDAC 5靶基因，如MEF 2C，它们的能力， 促进慢性疼痛状态的恢复，并增强抗抑郁药的疗效。我们将采用基因组 方法来确定其他HDAC 5目标，并测试它们在慢性疼痛和SNRI疗效中的作用。我们 研究结果将有助于提供有关控制基因表达的表观遗传和转录机制的见解。 维持慢性疼痛和对缓解疼痛药物的反应性。