Oxycodone, Neonatal Opioid Withdrawal Syndrome, and Adult Abuse Liability

过去十年来阿片类药物使用和滥用的急剧增加导致了 出生时依赖阿片类药物的婴儿。这些婴儿中的许多人将经历新生儿阿片类药物 戒断综合征（NOWS），因为他们的身体从高水平的阿片类药物中撤出， 母胎循环虽然在执行和 标准化治疗方案管理NOWS婴儿，仍然有显着的 对产前阿片类药物暴露的长期影响的担忧。此外，尚不清楚 NOWS的严重程度是否与成人结局有任何关系。动物研究可以 有助于确定潜在的长期脆弱性以及 神经发育可能会增加风险。产前羟考酮的临床前数据 暴露是有限的，这是不幸的，因为这种特殊的阿片类药物的广泛使用， 育龄妇女。我们最近开发了一种产前阿片类药物的动物模型， 妊娠前开始使用羟考酮自我给药的暴露 并持续整个怀孕期间。我们的初步研究结果表明， 在后代中，体重增加和出生后早期出现的超声波发声 期此外，我们还记录了转录调节因子的显著变化， 在这些后代中，出生后第1天的MeCP 2。目前的一系列研究将确定 大脑区域对MeCP 2的特异性影响在整个发育过程中持续存在，以及这些影响在多大程度上持续存在。 影响由母体摄入和/或产后戒断体征介导（具体目标1）。 研究还将确定母亲摄入量、产后戒断体征之间的关系 以及成年人的药物滥用倾向和冲动行为，因为这些代表了两种潜在的 临床发现中提示的漏洞（具体目标2）。最后，这些研究将 确定当女性突然停止使用时是否观察到类似的结果。 怀孕（强迫禁欲）或从羟考酮过渡到美沙酮或 丁丙诺啡，阿片类药物替代疗法中使用的两种常见药物（具体目标3）。 总的来说，这些研究将确定母亲自愿摄入 羟考酮、新生儿戒断体征和长期结局，并检验以下假设： 这些效应是由于MeCP 2表达变化诱导的表观遗传事件造成的。

The dramatic rise in opioid use and misuse over the past decade has resulted in an upsurge of infants born dependent upon opioids. Many of these babies will experience neonatal opioid withdrawal syndrome (NOWS) as their bodies withdraw from high levels of opioids in the maternal-fetal circulation. While there has been significant improvement in implementing and standardizing treatment protocols for managing NOWS infants, there remain significant concerns regarding the long-term impact of prenatal opioid exposure. Moreover it is unclear whether the severity of NOWS has any relationship with adult outcomes. Animal studies can be useful in identifying both potential long-term vulnerabilities as well as underlying changes in neurodevelopment that may confer increased risk. Preclinical data on prenatal oxycodone exposure are limited which is unfortunate given the widespread use of this particular opioid by women of reproductive age. We have recently developed an animal model of prenatal opioid exposure that utilizes self-administration of oxycodone with use beginning prior to conception and continuing throughout pregnancy. Our initial findings demonstrate dose-dependent changes in offspring body weight gain and ultrasonic vocalizations that emerge during the early postnatal period. In addition, we have documented significant changes in the transcriptional regulator MeCP2 on postnatal day 1 in these offspring. The current set of studies will determine whether brain region specific effects on MeCP2 persist across development and to what extent these effects are mediated by maternal intake and/or and postnatal withdrawal signs (Specific Aim 1). Studies will also determine the relationship between maternal intake, postnatal withdrawal signs and adult substance abuse liability and impulsive behavior, as these represent two potential vulnerabilities suggested in clinical findings (Specific Aim 2). Finally, these studies will determine whether similar outcomes are observed when females abruptly stop use during pregnancy (forced abstinence) or are transitioned from oxycodone to either methadone or buprenorphine, two common medications used in opioid replacement therapy (Specific Aim 3). Overall, these studies will determine the relationship between voluntary maternal intake of oxycodone, neonatal signs of withdrawal and long-term outcomes and test the hypothesis that these effects are due to epigenetic events induced by changes in MeCP2 expression.