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回路中的表观遗传和转录机制调节长期疼痛状态和对抗抑郁药物的反应。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。大部分的用于治疗这种疾病的疼痛样症状的药物显示出疗效低且副作用大。和，在阿片类药物类别中已有充分记录，当前的许多治疗方法都可能导致令人衰弱的成瘾。迫切需要开发更有效、耐受性更好的慢性病药物神经性疼痛。三环类抗抑郁药 (TCA) 和选择性血清素/去甲肾上腺素再摄取抑制剂 (SNRI) 具有抗异常疼痛和抗抑郁特性；然而，他们表现得很慢起效和长期使用常常伴随着严重的不良反应。了解介导 TCA 和 SNRI 作用的细胞内机制将有助于开发新的和更多的药物治疗神经性疼痛的有效药物。我们早期的研究结果确定了表观遗传修饰剂组蛋白脱乙酰酶 5 (HDAC5) 在模型中 TCA/SNRI 起效和功效中的作用神经性疼痛。伏隔核 (NAc) 中的 HDAC5 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 MEF2C。我们最近的初步研究结果表明，NAc 中 MEF2C 活性的促进可导致神经性疼痛的恢复州。展望未来，我们建议使用遗传小鼠模型、生化和基因组方法来了解慢性疼痛对 HDAC5 核活性以及与此相关的 NAc 回路的影响 HDAC5 行动。此外，我们将测试已知的 HDAC5 靶基因，例如 MEF2C，以确定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。我们将采用基因组学确定其他 HDAC5 靶点并测试其在慢性疼痛和 SNRI 功效中的作用的方法。我们的研究结果将有助于提供有关控制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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effective Attenuation of Adenosine A1R Signaling by Neurabin Requires Oligomerization of Neurabin.

Neurabin 有效减弱腺苷 A1R 信号传导需要 Neurabin 寡聚化。

DOI：
发表时间：
2017
期刊：
影响因子：
3.6
作者：
Chen, Yunjia;Booth, Christopher;Wang, Hongxia;Wang, Raymond X;Terzi, Dimitra;Zachariou, Venetia;Jiao, Kai;Zhang, Jin;Wang, Qin
通讯作者：
Wang, Qin

SARS-CoV-2 and Influenza A Virus Induce Longitudinal Transcriptomic Changes in Hamster Spinal Cord Tissue.

SARS-CoV-2 和甲型流感病毒诱导仓鼠脊髓组织的纵向转录组变化。

DOI：
发表时间：
2024-03-01
期刊：
影响因子：
3
作者：
Serafini, Randal A;Frere, Justin J;tenOever, Benjamin;Zachariou, Venetia
通讯作者：
Zachariou, Venetia

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model.

SARS-CoV-2 气道感染导致仓鼠模型中时间依赖性感觉异常。

DOI：
发表时间：
2022-08-19
期刊：
影响因子：
0
作者：
Serafini, Randal A;Frere, Justin J;Zimering, Jeffrey;Giosan, Ilinca M;Pryce, Kerri D;Golynker, Ilona;Panis, Maryline;Ruiz, Anne;tenOever, Benjamin;Zachariou, Venetia
通讯作者：
Zachariou, Venetia