Neonatal Opioid Exposure and Withdrawal: Molecular and Behavioral Consequences

项目摘要 在美国，孕妇使用阿片类药物是一个日益严重的公共卫生问题 各州。在宫内接触阿片类药物的婴儿表现出新生儿类阿片类药物的高风险 戒断综合症(NOWS)，身体戒断症状的组合，包括 尖叫、失眠、易怒、胃肠不适，最糟糕的情况是 病例，癫痫发作。这种综合征的复杂性被各种临床因素放大。 如产妇阿片类药物暴露持续时间、产妇多药、环境和 遗传学。宫内阿片类药物暴露的复杂性和NOWS使其很难 研究最终可能有助于早期诊断的潜在分子机制 和治疗。因此，我们开发了一种急需的3-小鼠模型 三个月的阿片类药物暴露和戒断。根据初步证据，我们假设 小胶质细胞激活和免疫介质在NOWS和NOWS的严重性中起作用 -阿片受体中的一个常见的单核苷酸多态调节这些效应。使用吗啡作为一种 典型的阿片类药物，我们将利用我们的模型来检验这些假设。首先，我们将全面 确定先天免疫系统在NOWS中的作用，并确定是否调节 神经炎症的治疗潜力通过药物治疗与抗 发炎药异丁司特。第二，正如最近的临床研究表明，基因组 编码阿片受体(OPRM1A118G)的基因变异可能会影响 现在严重程度，我们将使用包含等效OPRM1 A118G的鼠标行 SNP用于确定OPRM1基因对小胶质细胞激活和免疫的影响 调解人。使用我们的三个月阿片类药物暴露和戒断模型，我们将使用 TRAP-Seq，一种新的技术，用于检索核糖体复合体中的mRNA 主动翻译，在我们的情况下，在表达m-阿片受体的细胞中，以询问 阿片类药物暴露和戒断后转录组的变化。这个项目很可能 对这一领域产生持续和强大的影响，因为我们将解决 围产期接触阿片类药物导致NOWS的机制以及如何 遗传和免疫反应也起到了作用。

Project Summary Opioid use among pregnant women is a growing public health concern in the United States. Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of physical withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The complexity of this syndrome is amplified by a variety of clinical factors such as duration of maternal opioid exposure, maternal polypharmacy, environment, and genetics. The complexity of in utero opioid exposure and NOWS make it very difficult to investigate underlying molecular mechanisms that could ultimately inform early diagnosis and treatment. Therefore, we have developed a much needed mouse model of 3- trimester opioid exposure and withdrawal. Based on preliminary evidence, we hypothesize that microglia activation and immune mediators contribute to the severity of NOWS and a common SNP in the -opioid receptor modulates these effects. Using morphine as a prototypical opioid, we will exploit our model to test these hypotheses. First we will fully characterize the role of the innate immune system in NOWS and determine if regulation of neuroinflammation has therapeutic potential by pharmacological treatment with the anti- inflammatory drug, ibudilast. Second, as recent clinical findings suggest that genomic variation in the gene that encodes the -opioid receptor (Oprm1 A118G) may influence NOWS severity, we will use our mouse line that contains the equivalent Oprm1 A118G SNP to determine the impact of Oprm1 genetics on microglia activation and immune mediators. Using our model of 3-trimester opioid exposure and withdrawal we will use TRAP-Seq, a new technology for retrieving mRNAs within the ribosomal complex that are actively being translated, in our case in cells expressing m-opioid receptors, to interrogate the changing transcriptome following opioid exposure and withdrawal. This project is likely to have a sustained and powerful impact on the field because we will address mechanisms through which perinatal exposure to opiates results in NOWS, and how genetics and immune response contribute.