Newborns exposed to prenatal opioids often experience intense postnatal withdrawal after cessation of the opioid, called neonatal opioid withdrawal syndrome (NOWS), with limited pre- and postnatal therapeutic options available. In a prior study in pregnant mice we demonstrated that the peripherally selective neutral opioid antagonist, 6β-naltrexol (6BN), is a promising drug candidate for preventive prenatal treatment of NOWS. Here, we have developed methadone (MTD) treated pregnant guinea pigs as a physiologically more suitable model, enabling detection of robust spontaneous neonatal withdrawal. Prenatal MTD significantly aggravates two classic maternal separation stress behaviors in newborn guinea pigs: calling (vocalizing) and searching (locomotion) - natural attachment behaviors thought to be controlled by the endogenous opioid system. In addition, prenatal MTD significantly increases the levels of plasma cortisol in newborns, showing that cessation of MTD at birth engages the hypothalamic-pituitary-adrenal (HPA) axis. We find that co-administration of 6BN with MTD prevents these withdrawal symptoms in newborn pups with extreme potency (ID50 ~0.02 mg/kg), at doses unlikely to induce maternal or fetal withdrawal or to interfere with opioid antinociception based on many prior studies. Furthermore, we demonstrate a similarly high potency of 6BN in preventing opioid withdrawal in adult guinea pigs (ID50 = 0.01 mg/kg). This suggests a novel receptor mechanism to account for the selectively high potency of 6BN to suppress opioid dependence as compared to its low potency as a classical opioid antagonist. In conclusion, 6BN is an attractive compound for development of a preventive therapy for NOWS.

中文翻译：

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在怀孕的豚鼠模型中预防新生儿阿片类药物停药的药理作用。

暴露于产前阿片类药物的新生儿通常在戒断阿片类药物后经历剧烈的产后撤药，称为新生儿阿片类药物撤回综合征（NOWS），而产前和产后治疗选择有限。在对怀孕小鼠的先前研究中，我们证明了外周选择性中性阿片类药物拮抗剂6β-纳曲醇（6BN）是用于NOWS预防性产前治疗的有希望的候选药物。在这里，我们已经开发了美沙酮（MTD）处理过的豚鼠作为生理上更合适的模型，从而能够检测出强大的自发性新生儿退缩。产前MTD显着加重了新生豚鼠的两种经典的母体分离应激行为：呼唤（发声）和搜索（运动）-自然附着行为被认为受内源性阿片样物质系统控制。此外，产前MTD会显着增加新生儿的血浆皮质醇水平，表明出生时停止MTD参与了下丘脑-垂体-肾上腺（HPA）轴。根据许多先前的研究，我们发现6BN与MTD并用可预防新生仔仔的这些仔仔退出症状，这些仔仔具有极强的效力（ID50〜0.02 mg / kg），剂量不大可能诱发母体或胎儿仔仔退出或干扰阿片类药物的伤害感受。此外，我们证明了6BN在防止成年豚鼠阿片类药物戒断方面具有同样高的效力（ID50 = 0.01 mg / kg）。这暗示了一种新颖的受体机制，与6BN作为传统阿片拮抗剂的低效力相比，它有选择性地抑制了6BN的阿片依赖性。结论，