Study identifies the importance of modeling neonatal opioid withdrawal and brain adaptations in both sexes

(Boston)—The ongoing opioid epidemic in the United States has led to an increase in the incidence of Neonatal Opioid Withdrawal Syndrome (NOWS), a result of prenatal exposure to opioids. The effects of opioid exposure and withdrawal on infant neurodevelopment and behavior are not well characterized and clinical studies are limited in their ability to access brain tissue at appropriate intervals in order to fully understand the biological mechanisms mediating the effects of the prenatal exposure.

In a new study, researchers from Boston University School of Medicine (BUSM) have identified sex-dependent changes in gene expression in the brainstem during neonatal opioid withdrawal, suggesting that distinct neurobiological mechanisms, and by extension, distinct potential therapeutic targets, could underlie NOWS symptoms and their effective treatment in females versus males.

“This model can be used to understand the molecular mechanisms underlying NOWS symptoms and neurodevelopmental phenotypes induced by opioid perinatal exposure and could help in identifying new therapeutic targets to prevent or mitigate NOWS in humans,” explains first author Kristyn Borrelli, PhD candidate in neuroscience in the Laboratory of Addiction Genetics headed by Camron D. Bryant, PhD, associate professor of pharmacology and psychiatry at BUSM.

The researchers administered either morphine or saline in a mouse perinatal experimental model of the third trimester-equivalent in humans. They found that compared to saline-treated  neonates, morphine-exposed neonates displayed behavioral indications of opioid withdrawal, which in some cases were more pronounced in females. They also found that opioid-exposed neonates showed changes in gene expression in the brainstem and that these genes were linked to biological pathways that regulate development of the nervous system. “These findings suggest that prenatal opioid exposure, even during just this specific developmental time window, could compromise neurodevelopmental “wiring” of the brain and have long-term behavioral and health-related consequences,” said Borrelli.

The researchers hope this study will help facilitate the identification of therapeutic targets to prevent or mitigate the detrimental effects of prenatal opioid exposure on withdrawal and early developmental consequences. “Given the high incidence of NOWS, this work is a critical stepping stone to meet the urgent need for improved therapeutic approaches that minimize the long-term effects following prenatal exposure to opioids,” said Bryant.

These findings appear online in the journal eNeuro.

Funding for the study was provided by the  Spivack Center for Clinical and Translational Neuroscience; National Institute on Drug Abuse Grants U01-DA050243 and R01-DA-039168 (C.D.B.); National Heart, Lung, and Blood Institute Grant R01-150432 (R.W.L); Eunice Kennedy Shriver National Institute of Child Health and Human Development Grant R01-HD-096798 (E.W.); National Alliance for Research on Schizophrenia and Depression Young Investigator Grant 27202 (A.C-M.); and Boston University’s Undergraduate Research Opportunities Program (J.L.S.)