REST-mediated regulation of opioid receptors in chronic pain mouse models

慢性疼痛小鼠模型中阿片受体的 REST 介导调节

• 批准号: 10205014
• 负责人: SADHAN MAJUMDER
• 金额: $ 41.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205014
• 关键词: Affect; Afferent Neurons; Agonist; American; Analgesics; Antibodies; Attenuated; Binding; Chromatin; Chromatin Remodeling Factor; Chronic; Clinical; Complex; DNA Methylation; Disease; Epigenetic Process; Exhibits; FDA approved; Female; G9a histone methyltransferase; Gene Expression Regulation; Genes; Genetic Transcription; Goals; Histones; Hyperalgesia; Hypersensitivity; Knockout Mice; Link; Maintenance; Mediating; MicroRNAs; Mus; Nervous system structure; Neurons; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Peripheral nerve injury; Pharmaceutical Preparations; Process; Promoter Regions; RNA Polymerase II; Receptor Gene; Regulation; Repression; Rest; Role; Sertraline; Signal Transduction; Site; Small Interfering RNA; Spinal Ganglia; System; Testing; Transcription Repressor; United States National Institutes of Health; Untranslated RNA; VP 16; Wild Type Mouse; Work; addiction; base; cannabinoid receptor; chromatin modification; chronic neuropathic pain; chronic pain; conditional knockout; epigenomics; experimental study; gain of function; gender difference; genetic corepressor; genetic inhibitor; inhibitor/antagonist; innovation; insight; male; mouse model; nerve injury; nociceptin; novel; opioid epidemic; opioid use; overexpression; pain chronification; receptor; receptor expression; somatosensory

Project Summary Chronic neuropathic pain (CNP) is usually caused by disease or damage involving the somatosensory nervous system, adversely affecting millions of Americans. It is difficult to treat and remains a major clinical problem. Opioids, acting through opioid receptors (ORs: MOR for µ, KOR for κ, DOR for δ, NOP for nociceptin), trigger a complex signaling system and function as powerful analgesics. However, chronic opioid treatment causes hyperalgesia/analgesic tolerance and addiction, which have resulted in an opioid epidemic in the U.S. The opioid-induced hyperalgesia /analgesic tolerance (OIH/AT) and addiction can be modulated by many factors including OR expression levels and heteromer formation with different ORs (for example, MOR-DOR) or with other receptors such as the cannabinoid receptor (CNR1). Our long-term goal is to develop new strategies to enhance opioid analgesic effects and reduce opioid consumption for treatment of CNP. REST is a major epigenetic regulator. We and others have found that overexpression (OE) of REST in the dorsal root ganglion (DRG), causing repression of the MOR gene oprm1, is linked to the onset and maintenance of CNP. Our recent studies indicate that peripheral nerve injury in fact reduces opioid analgesia via the REST corepressor G9a-mediated chromatin repression of oprm1. Further, our preliminary studies suggest that MORs in DRG neurons are essential for OIH/AT. This would suggest that the REST-MOR axis in DRG neurons is a major mechanism regulating both CNP and OIH/AT. However, although the discovery of oprm1 as a REST target using a gene-by-gene approach is useful, it is unclear whether REST regulates the impacts of opioid analgesia in CNP or in OIH/AT by controlling the expression of other ORs or CNR1 or both of these processes. Our preliminary results suggest that REST differentially regulates expression of these receptors in DRG neurons. While it causes a decrease in the expression of MOR and DOR, it causes an increase in the expression of NOP and CNR1, perhaps by repressing the expression of an inhibitor of these genes such as a miRNA. To begin to generate comprehensive insights into the role of REST in CNP, we have now developed an innovative experimental system consisting of Rest conditional knock-out (cKO) mice and REST conditional OE (cOE) mice. Preliminary results indicate that whereas DRG-specific Rest cKO mice show attenuated pain hypersensitivity after nerve injury, DRG-specific REST cOE mice exhibit pain hypersensitivity even without nerve injury. Thus, the two contrasting mouse models recapitulate the chronic pain transition and provide a robust system in which to study mechanisms governing OR expression in primary sensory neurons in CNP and in OIH/AT. Here we propose to test the central hypothesis that REST in DRG neurons is involved in regulating opioid analgesia in CNP and in OIH/AT by governing ORs/CNR1 expression through epigenomic regulation of these genes. Thus, manipulation of REST in DRG neurons could be utilized to increase opioid analgesic efficacy and reduce opioid consumption. The project is responsive to PAR-18-742.

项目摘要 慢性神经病理性疼痛（CNP）通常由涉及躯体感觉神经的疾病或损伤引起 这对数百万美国人造成了不利影响。它很难治疗，仍然是一个主要的临床问题。 阿片类药物通过阿片受体发挥作用（OR：莫尔代表μ，KOR代表κ，DOR代表δ，NOP代表痛肽），触发A 复杂的信号系统和功能作为强大的止痛药。然而，长期阿片类药物治疗导致 痛觉过敏/镇痛耐受和成瘾，这导致了阿片类药物在美国的流行。 阿片诱导的痛觉过敏/镇痛耐受（OIH/AT）和成瘾可受到多种因素的调节 包括OR表达水平和具有不同OR（例如，MOR-DOR）或具有 其他受体，如大麻素受体（CNR 1）。我们的长期目标是制定新的战略， 增强阿片类镇痛作用并减少阿片类药物消耗以治疗CNP。REST是一个主要的 表观遗传调节因子我们和其他人已经发现，在背根神经节中REST的过表达（OE） (DRG)引起莫尔基因oprm 1的抑制，与CNP的发生和维持有关。我们 最近的研究表明，外周神经损伤实际上通过REST辅阻遏物减少阿片镇痛 g9 a介导的oprm 1染色质阻遏。此外，我们的初步研究表明，DRG中的MORs 神经元对OIH/AT是必需的。这表明DRG神经元中的REST-MOR轴是DRG神经元中的主要代谢途径。 调节CNP和OIH/AT的机制。然而，尽管oprm 1作为REST目标的发现 使用基因对基因的方法是有用的，目前还不清楚REST是否调节阿片类镇痛的影响。 在CNP或OIH/AT中通过控制其他OR或CNR 1或这两个过程的表达来实现。我们 初步结果表明，REST差异调节DRG神经元中这些受体的表达。 虽然它导致莫尔和DOR的表达减少，但它导致 NOP和CNR 1，可能通过抑制这些基因的抑制剂如miRNA的表达。到 开始对REST在CNP中的作用产生全面的见解，我们现在已经开发了一个创新的 由Rest条件性敲除（cKO）小鼠和REST条件性OE（cOE）组成的实验系统 小鼠初步结果表明，尽管DRG特异性Rest cKO小鼠显示疼痛减轻， 神经损伤后的超敏反应，DRG特异性REST cOE小鼠表现出疼痛超敏反应，即使没有 神经损伤因此，两种对比的小鼠模型概括了慢性疼痛转变，并提供了一种治疗慢性疼痛的方法。 一个强大的系统，在其中研究控制CNP中初级感觉神经元中OR表达的机制， 在OIH/AT。在这里，我们提出测试的中心假设，休息在DRG神经元参与调节 CNP和OIH/AT中阿片样物质镇痛通过表观基因组调控ORs/CNR 1表达 这些基因。因此，在DRG神经元中的REST的操纵可用于增加阿片镇痛 减少阿片类药物消耗。该项目响应PAR-18-742。