Oxycodone, Neonatal Opioid Withdrawal Syndrome, and Adult Abuse Liability

羟考酮、新生儿阿片类药物戒断综合征和成人滥用责任

• 批准号: 10404614
• 负责人: ELIZABETH M BYRNES
• 金额: $ 46.43万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404614
• 关键词: Abstinence; Address; Adolescence; Adult; Adult Children; Age; Animal Model; Animals; Behavioral; Biological; Biological Availability; Blood Circulation; Body Weight; Body Weights and Measures; Brain region; Buprenorphine; Child; Clinical; Conceptions; Data; Development; Dose; Drug Prescriptions; Epigenetic Process; Event; Female; Genetic Transcription; Glucocorticoids; Goals; Impulsive Behavior; Infant; Intake; Intravenous; Literature; Measures; Mediating; Metabolism; Methadone; Methyl-CpG-Binding Protein 2; Modeling; Modification; Neonatal; Neonatal Abstinence Syndrome; Opiate Addiction; Opioid; Opioid replacement therapy; Oral; Outcome; Oxycodone; Pattern; Pharmaceutical Preparations; Pre-Clinical Model; Pregnancy; Public Health; Rattus; Reproductive Biology; Risk; Self Administration; Severities; Standardization; Stress; Substance Use Disorder; Substance abuse problem; Symptoms; Testing; Treatment Protocols; Ultrasonics; Weight Gain; Withdrawal; Woman; Work; abuse liability; addiction liability; base; clinically relevant; early pregnancy; experience; experimental study; fetal; fetal opioid exposure; intergenerational; maternal opioid use; neonatal outcome; neurodevelopment; neurodevelopmental effect; offspring; opioid abuse; opioid exposure; opioid misuse; opioid use; opioid use disorder; opioid use in pregnancy; postnatal; postnatal development; postnatal period; pre-clinical; pregnant; prenatal; prescription opioid; prescription opioid abuse; reproductive; response; sex; species difference; symptom treatment; vocalization

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.

在过去的十年中，阿片类药物使用和滥用的急剧上升导致了 婴儿天生取决于阿片类药物。这些婴儿中有许多会经历新生儿阿片类药物 戒断综合征（现在），因为他们的身体从高水平的阿片类药物中退出 母亲循环。尽管实施和 标准化治疗方案用于管理婴儿，仍然存在重要的 对产前阿片类药物暴露的长期影响的担忧。而且还不清楚 现在的严重程度是否与成人结果有任何关系。动物研究可以是 有助于确定潜在的长期脆弱性以及基本变化 神经发育可能会增加风险。产前羟考酮的临床前数据 曝光受到限制，鉴于这种特定阿片类药物的广泛使用是不幸的 生殖年龄的妇女。我们最近开发了一种产前阿片类动物模型 利用羟考酮自我管理的暴露，从受孕之前开始使用 并在整个怀孕期间继续。我们的最初发现表明剂量依赖性变化 在后代体重增加和产后早期出现的超声声音中 时期。此外，我们已经记录了转录调节器的重大变化 在这些后代第1天的MECP2。当前的研究集将决定是否 大脑区域对MECP2的特定影响始终存在于开发过程中以及在多大程度上 效果是由母体摄入和/或产后戒断迹象介导的（特定目标1）。 研究还将确定产妇摄入，产后戒断迹象之间的关系 以及成人药物滥用责任和冲动行为，因为这些代表了两个潜力 临床发现中建议的漏洞（特定目标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（强制禁欲）或从羟考酮过渡到美沙酮或 丁丙诺啡，两种用于阿片类药物替代疗法的常见药物（特定目标3）。 总体而言，这些研究将确定自愿孕妇摄入量之间的关系 羟考酮，戒断和长期结局的新生儿迹象，并检验以下假设。 这些影响是由于MECP2表达变化引起的表观遗传事件。