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The ontogeny of P-glycoprotein in the developing human blood-brain barrier: implication for opioid toxicity in

Jessica Lam1,2, Stephanie Baello3, Majid Iqbal2

  • 1Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.

Pediatric Research
|June 19, 2015
PubMed

Insights

Neonatal brains have limited P-glycoprotein (P-gp) expression, increasing to adult levels by 3-6 months. This immaturity may cause opioid accumulation in the brain, explaining toxicity risks in newborns.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Developmental Biology

Background:

  • Neonates exhibit increased sensitivity to opioid central nervous system effects.
  • Immature P-glycoprotein (P-gp) development in neonates may impair morphine efflux from the brain.
  • Understanding P-gp ontogeny is crucial for neonatal opioid safety.

Purpose of the Study:

  • To investigate the developmental trajectory of P-glycoprotein (P-gp) expression in the human brain.
  • To correlate P-gp levels with gestational and postnatal age.
  • To elucidate the mechanisms behind neonatal opioid sensitivity.

Main Methods:

  • Human postmortem brain cortex samples were analyzed.
  • Samples represented various gestational ages (GA 20-26 wk, 36-40 wk) and postnatal ages (PNA 0-3 mo, 3-6 mo), plus adults.
  • Immunohistochemistry was used to quantify P-gp staining intensity.

Main Results:

  • P-gp staining intensity was significantly lower in neonates (GA 20-26 wk, GA 36-40 wk, PNA 0-3 mo) compared to adults.
  • P-gp expression showed a significant increase from PNA 0-3 mo to PNA 3-6 mo.
  • Adult P-gp levels were significantly higher than all neonatal and infant groups studied.

Conclusions:

  • Brain P-glycoprotein (P-gp) expression is low at birth and matures significantly by 3-6 months postnatal age.
  • Immature blood-brain barrier (BBB) P-gp in neonates can lead to morphine accumulation in the brain.
  • This developmental immaturity provides a mechanism for opioid toxicity observed in neonates, including those exposed via maternal breastfeeding.
Abstract

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