Microglia and Opioid Withdrawal

小胶质细胞和阿片类药物戒断

基本信息

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
项目类别：
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

项目摘要

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.

与海洛因等非法药物的使用和滥用有关的阿片类药物过量流行现象长期使用阿片类药物，即使是在医疗监督下也是如此。与阿片类药物戒断的耐受性和戒断风险的增加有关。综合征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，预防戒断综合症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）或许多严重问题的对症治疗例如腹泻、呕吐、脱水、痉挛、肌肉疼痛、失眠、烦躁和焦虑。当μ阿片类药物突然减少时，个人通常更愿意继续用药而不是面临戒断。受体激活是戒断的最直接原因，令人惊讶的是，我们对下游如何激活知之甚少生理过程导致了这种综合症的发生有很多严重的特征。因此，越来越多的证据表明阿片类药物耐受性和炎症状态并不令人惊讶。特别是急性戒断会产生神经炎症状态，这是症状的主要原因经验丰富。我们提出这样的假设：小胶质细胞是大脑中常驻的免疫细胞，在阿片类药物戒断以及这些细胞介导的炎症级联反应导致大部分戒断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（作为在我们将研究给予吗啡剂量逐渐增加的小鼠，然后再给予吗啡。沉淀退出，然后使用 RiboTag，一种从特定细胞中检索 RNA 的新技术类型，以探究阿片类药物戒断引起的小胶质细胞激活过程中发生的连续变化。其次，我们将评估是否可以通过抑制小胶质细胞激活来预防戒断综合症使用工程化的“DREADD”受体在戒断期间抑制小胶质细胞。我们实验室建立的最先进的转基因策略将使我们在该提案的最终目标是研究和调节急性阿片类药物戒断期间的小胶质细胞。确定小胶质细胞中可以预防与戒断相关的炎症的新分子靶标，导致开发新的治疗方法来缓解阿片类药物戒断，这将使戒断本身发生。更安全，并可能有助于激励成瘾者停止使用阿片类药物。