Sex-specific inflammatory and white matter effects of prenatal opioid exposure: a pilot study

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.

Sex differences in neonatal outcomes following prenatal opioid exposure

“…Several preclinical studies using cell cultures and animal models to examine oligodendrocyte maturation and function with exogenous opioid exposure during pregnancy demonstrate alterations in the timing of oligodendrocyte maturation and myelination ( 39 ). These studies further support emerging clinical literature that demonstrates white matter changes in infants with prenatal opioid exposure ( 32 , 40 ).…”

“…Opioid-exposed females, however, are not without risks. Despite less severe overt withdrawal, exposed females had a greater incidence of white matter hyperintensity in brain imaging than exposed males ( 32 ). Such white matter hyperintensity findings were accompanied by greater expression of proinflammatory genes, suggesting sex-specific proinflammatory effects of prenatal opioids and associated brain injury with a greater effect in females than males ( 32 ).…”

“…Despite less severe overt withdrawal, exposed females had a greater incidence of white matter hyperintensity in brain imaging than exposed males ( 32 ). Such white matter hyperintensity findings were accompanied by greater expression of proinflammatory genes, suggesting sex-specific proinflammatory effects of prenatal opioids and associated brain injury with a greater effect in females than males ( 32 ). Sex-specific proinflammatory effects on the brain and feeding regulation may alter the brain-gut axis and long-term health and developmental outcomes.…”