Prenatal Oxycodone Exposure Alters CNS Endothelin Receptor Expression in Neonatal Rats

Abstract

Prenatal opioid exposure such as oxycodone is linked to significant adverse effects on the developing brain. Endothelin (ET) and its receptors are involved in normal development of the central nervous system. Opioid tolerance and withdrawal are mediated through ET receptors. It is possible that adverse effect of oxycodone on the developing brain is mediated through ET receptors. We evaluated brain ETA and ETB receptor expression during postnatal development in rats with prenatal oxycodone exposure. Timed pregnant Sprague-Dawley rats received either oxycodone or placebo throughout gestation. After birth, male rat pups were sacrificed on postnatal day (PND) 1, 7, 14 or 28. Brain ETA and ETB receptor expression was determined by Western blot analysis. Oxycodone pups compared to placebo demonstrated congenital malformations of the face, mouth, and vertebrae at the time of birth [4/69 (5.7%) vs. 0/60 (0%); respectively] and intrauterine growth retardation [10/69 (15%) vs. 2/60 (3.3%); respectively]. On PND 28, oxycodone pups compared to placebo had lower body and kidney weight. ETA receptor expression in the oxycodone group was significantly higher compared to placebo on PND 1 (p=0.035), but was similar on PND 7, 14, or 28. ETB receptor expression decreased in oxycodone compared to placebo on PND 1 and 7 (p=0.001); and increased on PND 28 (p=0.002), but was similar on PND 14. Oxycodone-exposed rat pups had lower birth weight and postnatal weight gain and greater congenital malformations. ETB receptor expression is altered in the brain of oxycodone-treated rat pups indicating a possible delay in CNS development.

Neonatal abstinence syndrome and early childhood morbidity and mortality in Washington state: a retrospective cohort study

“…The majority of published research on NAS and/or antenatal opioid exposure focuses on neonatal and perinatal periods 6 , 9 – 18 . Whether these exposures have a long-term effect on childhood morbidity has not been elucidated; however, existing literature indicates that neonatal opioid exposure affects several neurobiologic processes in animal models 19 – 21 and results in neurocognitive and behavioral issues in humans 13 , 22 . Likewise, affected children may grow up in the setting of unstable living situations and other socioeconomic consequences of maternal substance use 13 , 23 which may be important mediators for adverse outcomes.…”

Enduring consequences of perinatal fentanyl exposure in mice

“…Few have exposed rodents to prenatal opioids other than morphine. [23][24][25][26][27][28][29] Here, we describe a novel model of perinatal fentanyl exposure by administering fentanyl in the drinking water of pregnant mouse dams until litters are weaned at postnatal day 21. This protocol resembles the entire human gestational period 30 and demonstrates its face validity to the human condition, in that it results in postnatal, adolescent and adult phenotypes reminiscent of those in exposed humans.…”

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure

“…However, a human study by Seaton et al has shown that oxy is concentrated in the breastmilk and offspring exposed via the breastmilk may receive less than 10% of a typical therapeutic oral infant dose (0.1-0.2 mg/kg) [32][33][34][35][36]. Despite this low dose, infant exposure to oxy via the breastmilk has been associated with central nervous system depression [37], and a number of animal studies have also revealed deficits in behavior and development associated with perinatal opioid exposure [12,[38][39][40]. Additionally, opiates can pass into the placenta and act on fetal opioid receptors [23][24][25].…”