Sunday, May 18, 2025
5/18/2025
Sex-specific Impact of Prenatal Opioids on Brain Reward Signaling and Neonatal Feeding Regulation - Project Summary/Abstract: Although Neonatal Abstinence Syndrome (NAS) is an urgent public health priority, the diagnosis and management of NAS remains challenging. This is primarily due to the multifactorial nature of NAS and the highly subjective measures to assess this condition. Males and females with NAS have distinct risk profiles, yet within the current paradigm they are managed uniformly. The limited understanding of long-term outcomes further compounds the problem and predisposes this population to a myriad of health issues. To address these knowledge gaps, the current proposal expands upon the molecular and behavioral data from our K12-funded pilot study to better understand the impact of prenatal opioid exposure. An early sign of withdrawal in opioid- exposed neonates is difficulty feeding followed by hyperphagia, which often precedes severe NAS and the need for pharmacotherapy. Using saliva collected immediately after birth, we showed higher expression of a key reward gene (DRD2) in opioid-exposed males compared to females. The expression of DRD2 also correlated with the caloric intake in opioid-exposed males who later developed severe NAS and required pharmacotherapy. These transcriptomic-behavioral data indicate that prenatal opioid exposure dysregulates brain reward signaling in a sex-specific manner, resulting in hyperphagia as a reward-seeking behavior that offsets the acute loss of opioids. Furthermore, opioid-exposed neonates have heightened expression of inflammatory genes (IL6, MCP1) that correlate with the expression of DRD2, particularly in females. Expanding on these preliminary results, the current proposal will examine if prenatal opioids dysregulate brain reward signaling and modulate pro-inflammatory pathways with increased sex-specific risks for hyperphagia and associated long-term cardiometabolic disorders. Our overarching goal is to understand changes in sex-specific reward and inflammatory gene expression in opioid-exposed neonates throughout the first year of life. The hypothesis will be tested in two aims: 1) Identify sex-specific effects of prenatal opioids on reward signaling and inflammation, 2) Evaluate effects of prenatal opioids on risk for subsequent cardiometabolic disorders. We will collect serial saliva samples from 56 opioid-exposed and 56 sex- and age-matched non-exposed neonates during the initial hospitalization and then in a subset of infants post hospital discharge up to 1 year of age to evaluate the expression of reward and inflammation genes. Early cardiometabolic risk will be assessed using serum lipid panels at 1 year of age, along with growth and nutritional data. Results will be analyzed by sex. The impact of this proposed project lies in the potential to advance the field with a more comprehensive understanding of the sex-specific impact of prenatal opioid exposure on the developing brain through non- invasive molecular analyses, enabling personalized medicine and longitudinal health monitoring.
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