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：
9314647
负责人：
Venetia Zachariou
金额：
$ 37.08万
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：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314647
关键词：
Absence of pain sensation Adverse effects Affective Affective Symptoms Analgesics Antidepressive Agents Antiparkinson Agents Antipsychotic Agents Anxiety Behavior Biochemical Biological Biological Neural Networks Brain Brain region Chronic Complex Corpus striatum structure Dependence Development Disease Drug effect disorder Drug usage Dysesthesias Epigenetic Process Event Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Expression Gene Expression Regulation Gene Transfer Genetic Human Hyperalgesia Investigation Laboratories Lead Mechanics Mediating Mental Depression Mind Modeling Molecular Molecular Biology Molecular Genetics Monitor Mood Disorders Mutant Strains Mice Names Nociception Norepinephrine Nucleus Accumbens Opiates Opioid Opioid Analgesics Pain Pain Disorder Patients Perception Pharmaceutical Preparations Play Property RGS9 protein Regulation Rewards Role Sensory Serotonin Signal Transduction Stress Structure Symptoms Testing Therapeutic Thermal Hyperalgesias Tricyclic Antidepressive Agents Viral Work addiction allodynia antidepressant effect brain circuitry chronic neuropathic pain chronic pain desensitization improved inhibitor/antagonist monoamine mouse model new therapeutic target novel novel strategies pain symptom painful neuropathy protein protein interaction psychostimulant public health relevance response reuptake tool transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): This project will elucidate antidepressant-induced changes on signal transduction in sensory and affective brain circuitry mediating neuropathic pain. Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the pain-like symptoms of this disorder have low efficacy, carry major side-effects and in the case of opioids may lead to debilitating physical addiction. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants and the selective, serotonin/norepinephrine reuptake inhibitors contain both antiallodynic and antidepressant properties. However, their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that RGS9-2, a potent regulator of striatal GPCR signaling amplitude and desensitization, plays a potent, modulatory role in the antiallodynic and antidepressant actions of TCAs. We will use genetic mouse models and gene transfer approaches to test our hypothesis that RGS9-2 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain models. In addition, we will use biochemical and molecular biological approaches to test our hypotheses on both the critical RGS9-2 protein-protein interactions modulating the effects of TCA and SNRI and the long-term epigenetic changes downstream of RGS9-2 in response to TCA and SNRI treatment. Finally, we will characterize antidepressant-induced and RGS9-2 modulated global gene regulation using RNA-sequencing in models of neuropathic pain. Our findings will clarify the mechanism by which GPCR signaling machinery in NAc modulates the effects of antidepressant drugs on the sensory and affective symptoms of neuropathic pain.

描述（由申请人提供）：该项目将阐明抗抑郁药引起的感觉和情感脑回路信号转导的变化，介导神经性疼痛。神经性疼痛是一种慢性疾病，其特征是感觉缺陷（机械性和冷性异常性疼痛、热痛觉过敏）和情绪障碍（焦虑和抑郁）。大多数用于治疗这种疾病的疼痛样症状的药物疗效都很差，并且具有严重的副作用，对于阿片类药物来说，可能会导致身体成瘾。因此，迫切需要开发更有效且耐受性更好的药物来治疗慢性神经性疼痛。三环类抗抑郁药和选择性血清素/去甲肾上腺素再摄取抑制剂具有抗异常疼痛和抗抑郁特性。然而，长期使用它们也会伴随严重的副作用。了解介导 TCA 和 SNRI 作用的细胞机制将有助于开发用于治疗神经性疼痛的新型且更有效的药物。我们实验室的初步研究结果表明，RGS9-2 是纹状体的有效调节剂。 GPCR 信号振幅和脱敏在 TCA 的抗异常疼痛和抗抑郁作用中发挥有效的调节作用。我们将使用遗传小鼠模型和基因转移方法来检验我们的假设，即 NAc 中的 RGS9-2 负向调节神经病理性疼痛模型中 TCA 和 SNRI 的作用。此外，我们将使用生化和分子生物学方法来测试我们的假设，即关键的 RGS9-2 蛋白质-蛋白质相互作用调节 TCA 和 SNRI 的影响，以及 RGS9-2 下游响应 TCA 和 SNRI 的长期表观遗传变化。 SNRI治疗。最后，我们将在神经性疼痛模型中使用 RNA 测序来表征抗抑郁药诱导的和 RGS9-2 调节的全局基因调控。我们的研究结果将阐明 NAc 中的 GPCR 信号机制调节抗抑郁药物对神经性疼痛的感觉和情感症状的影响的机制。