Cellular mechanisms of antidepressant drug actions in neuropathic pain models

该项目旨在阐明奖赏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。大多数 用于治疗这种疾病的疼痛症状的药物显示出低疗效和主要副作用。和, 在阿片类药物中，有充分的证据表明，目前的许多治疗方法都会导致虚弱的成瘾。 迫切需要开发更有效和更好的耐受性的药物来治疗慢性疾病 神经性疼痛。三环类抗抑郁药与选择性5-羟色胺/去甲肾上腺素再摄取 抑制剂(SNRI)同时具有抗痛觉过敏和抗抑郁的特性；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 治疗神经病理性疼痛的有效药物。我们早先的发现确定了一个关键的作用 表观遗传修饰剂组蛋白脱乙酰酶5(HDAC5)在TCAs/SNRIs模型中的作用起效和疗效 神经病理性疼痛。伏核(NAC)中的HDAC5与染色质复合体结合以抑制 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 初步研究结果表明，NAC中MEF2C活性的增强有助于神经病理性疼痛的恢复 各州。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核活动的影响，以及与其相关的NAC回路 HDAC5行动。此外，我们将测试已知的HDAC5靶基因，如MEF2C，以了解它们是否有能力 促进慢性疼痛状态的恢复，增强抗抑郁药物的疗效。我们将利用基因组 确定其他HDAC5靶点的方法，并测试它们在慢性疼痛和SNRI疗效中的作用。我们的 这些发现将有助于提供关于表观遗传和转录机制的见解，这些机制控制着 维持慢性疼痛和对止痛药的反应性。

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.