Differential Effects of Prenatal Buprenorphine and Methadone on Postnatal Growth and Gene Expression in the Nucleus Accumbens

Abstract

Methadone and buprenorphine are commonly prescribed during pregnancy to maintain recovery and prevent symptoms of withdrawal in women with opioid use disorder. Infants prenatally exposed to medications for opioid use disorder (MOUD), however, commonly show signs of neonatal opioid withdrawal syndrome (NOWS), which can include feeding-related issues like hyperphagia. To investigate the effects of prenatal MOUD exposure on feeding behavior, female Sprague-Dawley rats were implanted with osmotic minipumps filled with methadone, buprenorphine, or saline and subsequently mated. On postnatal day (PND) 1, buprenorphine- and methadone-exposed offspring weighed less than saline-exposed subjects. Throughout early postnatal development (PND2, 7, and 12), this reduction in weight persisted in buprenorphine, but not methadone, offspring. RNAscope in situ hybridization was then used to measure expression of genes in the nucleus accumbens (NAc) previously associated with hyperphagia in NOWS infants, including proopiomelanocortin (Pomc), neuropeptide Y2 receptors (Npy2r), and dopamine type 2 receptors (Drd2). Distinct developmental expression patterns were noted across the postnatal period, with few effects of MOUD; however, significantly lower Pomc expression was observed in methadone-exposed but not buprenorphine-exposed offspring. These findings demonstrate differential effects of methadone and buprenorphine on offspring development and gene expression, highlighting differences in offspring outcomes associated with these two MOUDs.