Zanni Giulia, Robinson-Drummer Patrese A, Dougher Ashlee A, Deutsch Hannah M, DeSalle Matthew J, Teplitsky David, Vemulapalli Aishwarya, Sullivan Regina M, Eisch Amelia J, Barr Gordon A
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, United States.
Department of Anesthesiology and Critical Care Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, United States; Department of Child and Adolescent Psychiatry, New York University Langone Medical Center, New York, NY, United States; Emotional Brain Institute, Nathan Kline Institute for Psychiatric Research, Orangeburg, NY, United States.
Drug Alcohol Depend. 2021 Apr 1;221:108628. doi: 10.1016/j.drugalcdep.2021.108628. Epub 2021 Feb 17.
The broad use/misuse of prescription opioids during pregnancy has resulted in a surge of infants with Neonatal Opioid Withdrawal Syndrome (NOWS). Short-term irritability and neurological complications are its hallmarks, but the long-term consequences are unknown.
A newly-developed preclinical model of oxycodone self-administration enables adult female rats to drink oxycodone (∼10/mg/kg/day) before and during pregnancy, and after delivery, and to maintain normal liquid intake, titrate dosing, and avoid withdrawal.
Oxycodone was detected in the serum of mothers and pups. Growth parameters in dams and pups and litter mass and size were similar to controls. There were no differences in paw retraction latency to a thermal stimulus between Oxycodone and Control pups at postnatal (PN) 2 or PN14. Oxycodone and Control pups had similar motor coordination, cliff avoidance, righting time, pivoting, and olfactory spatial learning from PN3 through PN13. Separation-induced ultrasonic vocalizations at PN8 revealed higher call frequency in Oxycodone pups relative to Control pups (p<0.031; Cohen's d=1.026). Finally, Oxycodone pups displayed withdrawal behaviors (p's<0.029; Cohen's d's>0.806), and Oxycodone males only vocalized more than Control pups in the first minute of testing (p's<0.050; Cohen's d's>.866). Significant effects were corroborated by estimation plots.
Our rat model of oral oxycodone self-administration in pregnancy shows exacerbated affect/social communication in pups in a sex-dependent manner but spared cognition and sensory-motor behaviors. This preclinical model reproduces selective aspects of human opioid use during pregnancy, enabling longitudinal analysis of how maternal oxycodone changes emotional behavior in the offspring.
孕期处方阿片类药物的广泛使用/滥用导致新生儿阿片类药物戒断综合征（NOWS）婴儿激增。短期易怒和神经并发症是其特征，但长期后果尚不清楚。
一种新开发的羟考酮自我给药临床前模型使成年雌性大鼠在怀孕前、怀孕期间和分娩后能够饮用羟考酮（约10毫克/千克/天），并保持正常液体摄入量、滴定给药量和避免戒断。
在母鼠和幼崽的血清中检测到了羟考酮。母鼠和幼崽的生长参数以及窝仔质量和大小与对照组相似。在出生后（PN）2天或PN14天时，羟考酮组和对照组幼崽对热刺激的爪缩回潜伏期没有差异。从PN3到PN13，羟考酮组和对照组幼崽在运动协调性、悬崖回避、翻身时间、旋转和嗅觉空间学习方面相似。PN8时分离诱导的超声波发声显示，羟考酮组幼崽的叫声频率高于对照组幼崽（p<0.031；科恩d值=1.026）。最后，羟考酮组幼崽表现出戒断行为（p值<0.029；科恩d值>0.806），并且只有羟考酮组雄性幼崽在测试的第一分钟内发声比对照组幼崽更多（p值<0.050；科恩d值>.866）。估计图证实了显著影响。
我们的孕期口服羟考酮自我给药大鼠模型显示，幼崽的情感/社交交流以性别依赖的方式加剧，但认知和感觉运动行为未受影响。这种临床前模型再现了孕期人类使用阿片类药物的某些方面，能够纵向分析母体羟考酮如何改变后代的情绪行为。
