The rates of opioid use disorder during pregnancy have more than quadrupled in the last decade, resulting in numerous infants suffering exposure to opioids during the perinatal period, a critical period of central nervous system (CNS) development. Despite increasing use, the characterization and definition of the molecular and cellular mechanisms of the long-term neurodevelopmental impacts of opioid exposure commencing in utero remains incomplete. Thus, in consideration of the looming public health crisis stemming from the multitude of infants with prenatal opioid exposure entering school age, we undertook an investigation of the effects of perinatal methadone exposure in a novel preclinical model. Specifically, we examined the effects of opioids on the developing brain to elucidate mechanisms of putative neural cell injury, to identify diagnostic biomarkers and to guide clinical studies of outcome and follow-up. We hypothesized that methadone would induce a pronounced inflammatory profile in both dams and their pups, and be associated with immune system dysfunction, sustained CNS injury, and altered cognition and executive function into adulthood. This investigation was conducted using a combination of cellular, molecular, biochemical, and clinically translatable biomarker, imaging and cognitive assessment platforms. Data reveal that perinatal methadone exposure increases inflammatory cytokines in the neonatal peripheral circulation, and reprograms and primes the immune system through sustained peripheral immune hyperactivity. In the brain, perinatal methadone exposure not only increases chemokines and cytokines throughout a crucial developmental period, but also alters microglia morphology consistent with activation, and upregulates TLR4 and MyD88 mRNA. This increase in neuroinflammation coincides with reduced myelin basic protein and altered neurofilament expression, as well as reduced structural coherence and significantly decreased fractional anisotropy on diffusion tensor imaging. In addition to this microstructural brain injury, adult rats exposed to methadone in the perinatal period have significant impairment in associative learning and executive control as assessed using touchscreen technology. Collectively, these data reveal a distinct systemic and neuroinflammatory signature associated with prenatal methadone exposure, suggestive of an altered CNS microenvironment, dysregulated developmental homeostasis, complex concurrent neural injury, and imaging and cognitive findings consistent with clinical literature. Further investigation is required to define appropriate therapies targeted at the neural injury and improve the long-term outcomes for this exceedingly vulnerable patient population.

中文翻译：

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产前阿片类药物暴露：下一个新生儿神经炎症疾病

在过去十年中，怀孕期间阿片类药物使用障碍的比率增加了四倍多，导致许多婴儿在围产期（中枢神经系统 (CNS) 发育的关键时期）暴露于阿片类药物。尽管使用越来越多，但对从子宫内开始接触阿片类药物的长期神经发育影响的分子和细胞机制的表征和定义仍然不完整。因此，考虑到因大量产前阿片类药物暴露婴儿进入学龄而引发的迫在眉睫的公共卫生危机，我们在新的临床前模型中对围产期美沙酮暴露的影响进行了调查。具体来说，我们检查了阿片类药物对发育中大脑的影响，以阐明假定的神经细胞损伤的机制，确定诊断生物标志物并指导临床研究结果和随访。我们假设美沙酮会在大坝及其幼崽中诱发明显的炎症特征，并与免疫系统功能障碍、持续的中枢神经系统损伤以及成年后认知和执行功能的改变有关。这项调查是使用细胞、分子、生化和临床可转化的生物标志物、成像和认知评估平台的组合进行的。数据显示，围产期美沙酮暴露会增加新生儿外周循环中的炎性细胞因子，并通过持续的外周免疫过度活跃来重新编程和启动免疫系统。在大脑中，围产期美沙酮暴露不仅会增加整个关键发育时期的趋化因子和细胞因子，但也会改变与激活一致的小胶质细胞形态，并上调 TLR4 和 MyD88 mRNA。这种神经炎症的增加与髓鞘碱性蛋白的减少和神经丝表达的改变，以及结构连贯性的降低和扩散张量成像的各向异性分数显着降低相吻合。除了这种微结构脑损伤外，在围产期暴露于美沙酮的成年大鼠在使用触摸屏技术评估的联想学习和执行控制方面有显着损害。总的来说，这些数据揭示了与产前美沙酮暴露相关的独特全身性和神经炎症特征，表明中枢神经系统微环境改变、发育稳态失调、复杂的并发神经损伤、影像学和认知发现与临床文献一致。需要进一步调查以确定针对神经损伤的适当疗法，并改善这一极其脆弱的患者群体的长期结果。