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。 States.在子宫内暴露于阿片类药物的婴儿患新生儿阿片类药物的风险很高 戒断综合征（NOWS），一种身体戒断症状的组合，包括 高音调的哭泣，失眠，易怒，胃肠道不适，最严重的是 病例癫痫这种综合征的复杂性被各种临床因素放大 如母体阿片类药物暴露持续时间、母体多种用药、环境， 遗传学子宫内阿片类药物暴露和NOWS的复杂性使得很难 研究可能最终为早期诊断提供信息的潜在分子机制 和治疗。因此，我们开发了一种急需的3- 妊娠期阿片类药物暴露和戒断。基于初步证据，我们假设 小胶质细胞激活和免疫介质有助于NOWS的严重性， β-阿片受体中的一种常见SNP调节这些作用。使用吗啡作为 原型阿片类药物，我们将利用我们的模型来测试这些假设。首先，我们将全面 描述先天免疫系统在NOWS中的作用，并确定是否调节 的神经炎症具有治疗潜力的药物治疗与抗- 消炎药异丁司特其次，最近的临床研究结果表明， 编码β-阿片受体（Oprm 1 A118 G）的基因的变异可能会影响 NOWS严重性，我们将使用包含等效Oprm 1 A118 G的鼠标线 SNP以确定Oprm 1遗传学对小胶质细胞活化和免疫的影响 调解员使用我们的3个月阿片类药物暴露和戒断模型，我们将使用 TRAP-Seq是一种新技术，用于检索核糖体复合物中的mRNA， 在我们的情况下，在表达m-阿片受体的细胞中， 阿片类药物暴露和戒断后转录组的变化。这个项目很可能 对该领域产生持续和强大的影响，因为我们将解决 围产期暴露于阿片类药物导致NOWS的机制，以及如何 遗传学和免疫反应的影响。

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.