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

基本信息

批准号：
10830180
负责人：
Venetia Zachariou
金额：
$ 36.34万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10830180
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 Histone Deacetylase Inhibitor Hypersensitivity Intervention Knock-out 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 gene repression inhibitor insight knock-down mechanical allodynia men&apos s group monoamine mouse model myocyte-specific enhancer-binding-factor 2C 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 time use transcription factor transcriptome sequencing

项目摘要

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电路中的表观遗传和转录机制，这些机制介导长期疼痛状态和对抗抑郁药的反应。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。大多数用于治疗这种疾病的疼痛症状的药物表现出低功效和主要副作用。和，在阿片类药物类别中，许多当前的治疗方法都有良好的文献记载，可能导致令人衰弱的成瘾。迫切需要开发更有效，更耐受的慢性药物神经性疼痛。三环抗抑郁药（TCA）和选择性，5-羟色胺/去甲肾上腺素的再摄取抑制剂（SNRIS）既包含抗溶菌和抗抑郁剂的特性；但是，它们表现缓慢动作发作和长期使用通常会伴随着严重的不良反应。了解介导TCA和SNRI的作用的细胞内机制将有助于新颖的发展以及更多有效治疗神经性疼痛的药物。我们较早的发现确定了 TCA/SNRI在模型中的作用和功效开始，表观遗传修饰剂组蛋白脱乙酰基酶5（HDAC5）神经性疼痛。伏隔核中的HDAC5（NAC）与染色质复合物结合以抑制影响突触功能的几种基因的表达，包括转录因子MEF2C。我们最近初步发现表明，在NAC中促进MEF2C活性导致神经性疼痛恢复国家。向前迈进，我们建议使用遗传小鼠模型，生化和基因组方法了解慢性疼痛对HDAC5核活动的影响，以及与NAC电路有关 HDAC5动作。此外，我们将测试已知的HDAC5靶基因，例如MEF2C，以便它们的能力促进慢性疼痛状态的恢复并增强抗抑郁药的功效。我们将采用基因组确定其他HDAC5靶标并测试其在慢性疼痛和SNRI功效中的作用的方法。我们的调查结果将有助于提供有关控制的表观遗传和转录机制的见解维持慢性疼痛和对疼痛疼痛药物的反应。