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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：
10532060
负责人：
Venetia Zachariou
金额：
$ 0.57万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532060
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&apos 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

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.

本项目旨在阐明奖赏脑回路的表观遗传和转录机制