Microglia and Opioid Withdrawal

小胶质细胞和阿片类药物戒断

• 批准号: 9524850
• 负责人: John F Neumaier
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9524850
• 关键词: Acute; Analgesics; Animals; Anxiety; Benzodiazepines; Biological; Brain; Cells; Cessation of life; Chronic; Clinical; Clonidine; Coupled; Data; Decision Making; Dehydration; Development; Diarrhea; Disease; Disincentive; Dose; Drug Receptors; Drug usage; Engineering; Epidemic; Exposure to; Face; GTP-Binding Proteins; Goals; Heroin; Hyperalgesia; Immune; Immunohistochemistry; In Situ Hybridization; Individual; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligands; Measures; Mediating; Medical; Methadone; Methods; Microglia; Molecular; Molecular Target; Morphine; Motivation; Mus; Muscle; Muscle Cramp; Myalgia; Naloxone; Narcotics; Non-Steroidal Anti-Inflammatory Agents; Opiate Addiction; Opioid; Overdose; Pathway interactions; Pharmaceutical Preparations; Physiological; Physiological Processes; Proteins; Psychological Impact; RNA; RNA analysis; Receptor Activation; Relapse; RiboTag; Ribosomes; Risk; Role; Saline; Sampling; Schedule; Severities; Signal Transduction; Sleeplessness; Specific qualifier value; Substance Withdrawal Syndrome; Supervision; Symptoms; Syndrome; System; Technology; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translating; Translations; Universities; Vomiting; Washington; Withdrawal; Withdrawal Symptom; cell type; cohort; conditioning; designer receptors exclusively activated by designer drugs; drug reward; experience; experimental study; illicit drug use; in vivo; mu opioid receptors; neuroinflammation; new technology; novel; opiate tolerance; opioid abuse; opioid epidemic; opioid overdose; opioid use; opioid withdrawal; prevent; psychologic; response; social; tool; transcriptome sequencing; translatome

There is an epidemic of opioid overdoses associated with the use of illicit drugs such as heroin and the misuse of prescribed narcotic pain medications. Chronic use of opioids, even when under medical supervision, is associated with the development of tolerance and escalating risk of withdrawal. The opioid withdrawal syndrome is a serious medical problem that can become a major reason why addicts keep using opioid drugs. Currently the only treatments to prevent the withdrawal syndrome are either continuing to take opioids (including substitution drugs such as methadone) or symptomatic management of the many severe problems such as diarrhea, vomiting, dehydration, cramping, muscle pain, insomnia, irritability, and anxiety. Addicted individuals often prefer to continue drugs rather than face withdrawal. While the sudden reduction in mu opioid receptor activation is the proximal cause of withdrawal, surprisingly little is known about how downstream physiological processes contribute to the syndrome. Being “dope-sick” has many attributes of a severe inflammatory state. Thus, it is not surprising that evidence is accumulating that both opioid tolerance and especially acute withdrawal produce a neuroinflammatory state that is a major contributor to the symptoms experienced. We propose the hypothesis that microglia, the resident immune cells in the brain, become activated during opioid withdrawal and that the inflammatory cascades mediated by these cells lead to much of the withdrawal syndrome. We will test this idea using two strategies. First, we will measure the RNAs in microglia cells that are actively being translated to make protein (as indicators of the biological pathways that are activated in these cells during withdrawal). We will investigate mice given escalating doses of morphine followed by precipitated withdrawal and then use RiboTag, a new technology for retrieving the RNA from specific cell types, to interrogate the sequential changes occurring during microglial activation from opioid withdrawal. Second, we will assess whether the withdrawal syndrome can be prevented by inhibiting microglial activation using engineered “DREADD” receptors to inhibit microglia during withdrawal. These experiments will utilize state of the art transgenic strategies that are established in our lab and will allow us unprecedented precision in investigating and modulating microglia during acute opioid withdrawal. The ultimate goal of this proposal is to identify novel molecular targets in microglia that can prevent the inflammation associated with withdrawal, leading to the development of new treatments to mitigate opioid withdrawal. This will make withdrawal itself safer and potentially contribute to the motivation of addicted individuals to discontinue opioid use.

阿片类药物过量与海洛因等非法药物的使用和滥用有关， 处方的麻醉止痛药。长期使用阿片类药物，即使在医疗监督下， 与耐受性的发展和撤退风险的增加有关。阿片类药物戒断 综合症是一个严重的医学问题，可能成为成瘾者继续使用阿片类药物的主要原因。 目前，预防戒断综合征的唯一治疗方法是继续服用阿片类药物 （包括美沙酮等替代药物）或对症治疗许多严重问题 如腹泻、呕吐、脱水、痉挛、肌肉疼痛、失眠、易怒和焦虑。上瘾 个人往往宁愿继续吸毒，也不愿面临戒断。而μ阿片类药物的突然减少 受体激活是戒断的近端原因，令人惊讶的是，对下游如何 生理过程导致了该综合征。“毒瘾”有很多严重的特征， 炎症状态因此，毫不奇怪，越来越多的证据表明阿片类药物耐受性和 特别是急性戒断会产生神经炎性状态 经验丰富。 我们提出的假设是，小胶质细胞，在大脑中的居民免疫细胞，成为激活过程中， 阿片类药物戒断，这些细胞介导的炎症级联反应导致大部分戒断 综合征我们将使用两种策略来测试这个想法。首先，我们将测量小胶质细胞中的RNA， 正在积极地被翻译以制造蛋白质（作为生物途径的指示剂， 这些细胞在撤回期间）。我们将研究小鼠给予递增剂量的吗啡， 沉淀提取，然后使用RiboTag，一种从特定细胞中提取RNA的新技术 类型，询问从阿片类药物戒断小胶质细胞激活过程中发生的顺序变化。 其次，我们将评估是否可以通过抑制小胶质细胞的激活来预防戒断综合征 使用工程“DREADD”受体来抑制戒断期间的小胶质细胞。这些实验将利用 最先进的转基因策略，在我们的实验室建立，将使我们前所未有的精度， 研究和调节急性阿片类药物戒断期间的小胶质细胞。这项建议的最终目的是 在小胶质细胞中确定新的分子靶点，可以预防与戒断相关的炎症， 导致开发新的治疗方法来减轻阿片类药物戒断。这将使撤退本身 更安全，并可能有助于成瘾者停止使用阿片类药物的动机。