Abstract
Background
Preclinical data demonstrate that opioids modulate brain reward signaling through an inflammatory cascade, but this relationship has yet to be studied in opioid-exposed neonates.
Methods
Saliva samples of 54 opioid-exposed and sex- and age-matched non-exposed neonates underwent transcriptomic analysis of inflammatory and reward genes. A subset of 22 neonates underwent brain magnetic resonance imaging (MRI) to evaluate white matter injury commonly associated with inflammatory response. Gene expression and brain MRI were compared between opioid- and non-exposed neonates and further stratified by sex and pharmacotherapy need.
Results
Opioid-exposed females regardless of pharmacotherapy need had higher expression of inflammatory genes than their male counterparts, with notable differences in the expression of CCL2 and CXCL1 in females requiring pharmacotherapy (p = 0.01 and 0.06, respectively). Opioid-exposed males requiring pharmacotherapy had higher expression of DRD2 than exposed females (p = 0.07), validating our prior research. Higher expression of IL1β, IL6, TNFα, and IL10 was seen in opioid-exposed neonates with T1 white matter hyperintensity (WMH) compared to exposed neonates without WMH (p < 0.05).
Conclusion
Prenatal opioid exposure may promote inflammation resulting in changes in reward signaling and white matter injury in the developing brain, with unique sex-specific effects. The actions of opioids through non-neuronal pathways need further investigation.
Impact
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Opioid-exposed neonates are at risk for punctate T1 white matter hyperintensity (WMH).
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Females carry a greater propensity for WMH.
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Salivary transcriptomic data showed significantly higher expression of inflammatory genes in opioid-exposed neonates with WMH than those without WMH, irrespective of pharmacotherapy need.
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Adding to prior studies, our findings suggest that prenatal opioid exposure may modulate white matter injury and reward signaling through a pro-inflammatory process that is sex specific.
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This novel study highlights the short-term molecular and structural effects of prenatal opioids and the need to elucidate the long-term impact of prenatal opioid exposure.
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Data availability
Materials described in the manuscript, including all relevant raw data, are available for research and non-commercial purposes upon reasonable request, without breaching participant confidentiality.
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Acknowledgements
We would like to thank all the families for participating in this study. We also thank the entire staff at the Tufts Shields MRI for their assistance in organizing and acquiring the images.
Funding
This study received funding from K12 Building Interdisciplinary Research for Careers in Women’s Health (BIRCWH) Grant #5K12HD092535-05, Charles H. Hood Foundation Child Health Research Grant, and Tufts Tiny Feet Funds. The project was supported by the National Center for Advancing Translational Sciences, NIH, #UL1TR002544. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.
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Conception and design: E.Y., N.M., T.T., T.K.-T., J.L.M. Acquisition of data: E.Y., N.M. Analysis and interpretation of data: E.Y., J.L.B. Drafting the article: E.Y. Critical revision: E.Y., N.M., T.T., T.K.-T., J.L.B., J.M.D., J.L.M. Final approval of the version to be published: E.Y., N.M., T.T., T.K.-T., J.L.B., J.M.D., J.L.M.
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Yen, E., Madan, N., Tarui, T. et al. Sex-specific inflammatory and white matter effects of prenatal opioid exposure: a pilot study. Pediatr Res 93, 604–611 (2023). https://doi.org/10.1038/s41390-022-02357-5
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DOI: https://doi.org/10.1038/s41390-022-02357-5
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