Section for Drug Abuse Research, Department of Forensic Sciences (M.K., I.L.B., J.M.A.) and Department of Neonatal Intensive Care (T.S.), Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine (M.K., T.S.), Department of Pharmacy, Faculty of Mathematics and Natural Sciences (J.M.A.), and Institute of Basic Medical Sciences, Faculty of Medicine (I.L.B.), University of Oslo, Oslo, Norway
Section for Drug Abuse Research, Department of Forensic Sciences (M.K., I.L.B., J.M.A.) and Department of Neonatal Intensive Care (T.S.), Oslo University Hospital, and Institute of Clinical Medicine, Faculty of Medicine (M.K., T.S.), Department of Pharmacy, Faculty of Mathematics and Natural Sciences (J.M.A.), and Institute of Basic Medical Sciences, Faculty of Medicine (I.L.B.), University of Oslo, Oslo, Norway.
J Pharmacol Exp Ther. 2019 Oct;371(1):130-137. doi: 10.1124/jpet.119.259531. Epub 2019 Jul 29.
Experimental animal studies are valuable in revealing a causal relationship between prenatal exposure to opioid maintenance treatment (OMT) and subsequent effects; however, previous animal studies of OMT during pregnancy have been criticized for their lack of clinical relevance because of their use of high drug doses and the absence of pharmacokinetic data. Hence, the aim of this study was to determine blood and brain concentrations in rat dams, fetuses, and offspring after continuous maternal exposure to methadone or buprenorphine during gestation and to examine the offspring for neonatal outcomes and withdrawal symptoms. Female rats were implanted with a 28-day osmotic minipump delivering methadone (10 mg/kg per day), buprenorphine (1 mg/kg per day) or vehicle 5 days before mating. Continuous exposure to methadone or buprenorphine induced stable blood concentrations in the dams of 0.25 ± 0.02 M and 5.65 ± 0.16 nM, respectively. The fetal brain concentration of methadone (1.89 ± 0.35 nmol/g) was twice as high as that in the maternal brain, whereas the fetal brain concentration of buprenorphine (20.02 ± 4.97 pmol/g) was one-third the maternal brain concentration. The opioids remained in the offspring brain several days after the exposure ceased. Offspring prenatally exposed to methadone, but not buprenorphine, displayed reduced body weight and length and increased corticosterone levels. No significant changes in ultrasonic vocalizations were revealed. Our data in rat fetuses and neonates indicate that OMT with buprenorphine may be a better choice than methadone during pregnancy. SIGNIFICANCE STATEMENT: Concern has been raised about the use of opioid maintenance treatment during pregnancy because of the important role of the endogenous opioid system in brain development. Here, we show that the methadone concentration in the fetal rat brain was twice as high as that in the maternal brain, whereas the buprenorphine concentration was one-third the maternal concentration. Furthermore, buprenorphine allowed more favorable birth outcomes, suggesting that buprenorphine may be a better choice during pregnancy.
实验动物研究对于揭示产前暴露于阿片类药物维持治疗（OMT）与随后的影响之间的因果关系具有重要价值；然而，由于先前的动物研究使用了高剂量的药物且缺乏药代动力学数据，因此其与临床相关性较差，因此受到了批评。因此，本研究的目的是确定孕鼠、胎儿和仔鼠在连续接受美沙酮或丁丙诺啡维持治疗后的血液和大脑浓度，并检查仔鼠的新生儿结局和戒断症状。雌性大鼠在交配前 5 天植入一个 28 天的渗透微型泵，以输送美沙酮（每天 10mg/kg）、丁丙诺啡（每天 1mg/kg）或载体。连续暴露于美沙酮或丁丙诺啡可使母体血液浓度分别稳定在 0.25±0.02μM 和 5.65±0.16nM。美沙酮在胎儿大脑中的浓度（1.89±0.35nmol/g）是母体大脑中的两倍，而丁丙诺啡在胎儿大脑中的浓度（20.02±4.97pmol/g）是母体大脑中的三分之一。停止暴露后，阿片类药物仍存在于仔鼠的大脑中数天。与丁丙诺啡相比，产前暴露于美沙酮的仔鼠体重和体长降低，皮质酮水平升高，但超声发声没有明显变化。我们在大鼠胎儿和新生儿中的数据表明，与美沙酮相比，丁丙诺啡可能是妊娠期间维持治疗的更好选择。
由于内源性阿片系统在大脑发育中的重要作用，人们对妊娠期间使用阿片类药物维持治疗表示担忧。在这里，我们显示美沙酮在胎鼠大脑中的浓度是母体大脑中的两倍，而丁丙诺啡的浓度是母体的三分之一。此外，丁丙诺啡允许更好的出生结局，这表明丁丙诺啡在妊娠期间可能是更好的选择。
