Salivary Transcriptomic Analysis to Understand Sex-Dependent Inflammatory Effects of Prenatal Opioid Exposure on the Brain Reward Signaling

Key Words: Gene expression, Neonatal saliva, Inflammation, Brain reward signaling, Prenatal opioid exposure, Neonatal abstinence syndrome, Neonatal opioid withdrawal syndrome

Infants born to mothers who use opioid drugs during pregnancy are at risk for withdrawal signs, known as neonatal abstinence syndrome (NAS). Hospital staff determines the need to start medication for severe NAS based on scoring tools that rely on the staff’s perception, often leading to inconsistent decision making. A common withdrawal sign is overeating, with opioid-exposed infants consuming 1.5 to 2 times more calories than non-exposed infants. To develop a more uniform tool to assess NAS, our laboratory analyzed neonatal saliva samples to measure biomarkers involved in feeding regulation. We hypothesized that infants who develop severe withdrawal signs and excessive eating would have early dysregulation of these feeding biomarkers.

Our research demonstrated that opioid-exposed boys who developed more severe withdrawal and required medication had a significantly higher expression of a brain biomarker called DRD2 (dopamine receptor type 2) than girls. DRD2 provides rewarding signals in response to opioids and food, and may explain why these opioid-exposed boys with elevated DRD2 expression also ate excessively. This finding implies that DRD2 may be a biomarker that could identify which infants will develop worse withdrawal and require medication. This result also suggests that excessive eating may be the primary way these infants obtain reward signals previously provided by maternal opioid use. We also recently found that girls with more severe withdrawal had higher inflammation markers in their saliva than boys. Our finding supports animal studies that showed opioids activate inflammation in the brain, which may disturb the reward signaling provided by DRD2 and predispose to future addiction. These exciting preliminary data lay the foundation for our Charles H. Hood application, where we will measure salivary expression of DRD2 and inflammation biomarkers in opioid-exposed infants throughout their entire withdrawal course. This important study will improve our understanding of the underlying mechanisms of withdrawal in opioid-exposed infants, help hospital staff more accurately determine which infants will require medication, and reinforce the need to perform a long-term follow-up for adverse, but potentially modifiable, behaviors.