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: 9977491
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977491
• 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; 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。 系统，对数百万美国人产生了不利影响。它很难治疗，仍然是一个主要的临床问题。 通过阿片受体起作用的阿片类药物(ORs：µ为MOR，κ为KOR，δ为DOR，伤害素为NOP)，触发 复杂的信号系统和强大的镇痛剂功能。然而，慢性阿片类药物治疗导致 痛觉过敏/止痛药耐受性和成瘾，导致阿片类药物在美国流行 阿片类药物诱导的痛觉过敏/镇痛耐受(OIH/AT)和成瘾可受多种因素的调节 包括OR表达水平和具有不同OR的异构体形成(例如，MOR-DOR)或 其他受体，如大麻素受体(CNR1)。我们的长期目标是制定新的战略，以 提高阿片类药物的镇痛效果，减少阿片类药物在CNP中的应用。休息是主要的 表观遗传调节因子。我们和其他人发现，REST在背根神经节的过度表达(OE) 引起MOR基因OPRM1抑制的DRG与CNP的发生和维持有关。我们的 最近的研究表明，周围神经损伤实际上通过静息辅助抑制物减少了阿片类药物的镇痛作用 G9a介导的OPRM1染色质抑制。此外，我们的初步研究表明，DRG中的MORS 神经元在OIH/AT中是必不可少的。这可能表明DRG神经元的REST-MOR轴是一个主要的 CNP和OIH/AT的调节机制。然而，尽管发现OPRM1作为REST目标 使用逐个基因的方法是有用的，目前尚不清楚REST是否调节阿片类止痛的影响 在CNP或OIH/AT中，通过控制其他ORs或CNR1的表达，或同时控制这两个过程。我们的 初步结果表明，REST对DRG神经元中这些受体的表达有不同的调节作用。 虽然它导致MOR和DOR的表达减少，但它导致MOR和DOR的表达增加 NOP和CNR1，可能是通过抑制这些基因的抑制物，如miRNA的表达。至 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 由静息条件基因敲除(CKO)小鼠和静息条件OE(COE)组成的实验系统 老鼠。初步结果表明，虽然DRG特异性的静息CKO小鼠表现出减轻的疼痛 神经损伤后的超敏反应，DRG特异性静息COE小鼠即使没有表现出疼痛过敏 神经损伤。因此，两种不同的小鼠模型概括了慢性疼痛的转变，并提供了一种 研究CNP和CNP初级感觉神经元中OR表达调控机制的强健系统 在OIH/AT。在这里，我们建议检验中枢假说，即DRG神经元中的休息参与调节 表观基因组调控ORS/CNR1基因表达对CNP和OIH/AT阿片类药物的镇痛作用 这些基因。因此，操纵DRG神经元的静息可用于增加阿片类止痛剂。 提高疗效，减少阿片类药物的消耗。该项目是对PAR-18-742的响应。