Oxycodone, Neonatal Opioid Withdrawal Syndrome, and Adult Abuse Liability

The dramatic rise in opioid use and misuse over the past decade has resulted in an upsurge of
infants born dependent upon opioids. Many of these babies will experience neonatal opioid
withdrawal syndrome (NOWS) as their bodies withdraw from high levels of opioids in the
maternal-fetal circulation. While there has been significant improvement in implementing and
standardizing treatment protocols for managing NOWS infants, there remain significant
concerns regarding the long-term impact of prenatal opioid exposure. Moreover it is unclear
whether the severity of NOWS has any relationship with adult outcomes. Animal studies can be
useful in identifying both potential long-term vulnerabilities as well as underlying changes in
neurodevelopment that may confer increased risk. Preclinical data on prenatal oxycodone
exposure are limited which is unfortunate given the widespread use of this particular opioid by
women of reproductive age. We have recently developed an animal model of prenatal opioid
exposure that utilizes self-administration of oxycodone with use beginning prior to conception
and continuing throughout pregnancy. Our initial findings demonstrate dose-dependent changes
in offspring body weight gain and ultrasonic vocalizations that emerge during the early postnatal
period. In addition, we have documented significant changes in the transcriptional regulator
MeCP2 on postnatal day 1 in these offspring. The current set of studies will determine whether
brain region specific effects on MeCP2 persist across development and to what extent these
effects are mediated by maternal intake and/or and postnatal withdrawal signs (Specific Aim 1).
Studies will also determine the relationship between maternal intake, postnatal withdrawal signs
and adult substance abuse liability and impulsive behavior, as these represent two potential
vulnerabilities suggested in clinical findings (Specific Aim 2). Finally, these studies will
determine whether similar outcomes are observed when females abruptly stop use during
pregnancy (forced abstinence) or are transitioned from oxycodone to either methadone or
buprenorphine, two common medications used in opioid replacement therapy (Specific Aim 3).
Overall, these studies will determine the relationship between voluntary maternal intake of
oxycodone, neonatal signs of withdrawal and long-term outcomes and test the hypothesis that
these effects are due to epigenetic events induced by changes in MeCP2 expression.

Grant Number: 3R01DA049531-05S1
NIH Institute/Center: NIH
Principal Investigator: ELIZABETH BYRNES