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

Jessica Lam, Stephanie Baello, Majid Iqbal, Lauren E. Kelly, Patrick T. Shannon, David Chitayat, Stephen G. Matthews, Gideon Koren

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Background:Neonates have been shown to have a heightened sensitivity to the central depressive effects of opioids compared to older infants and adults. The limited development of P-glycoprotein (P-gp) may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. The objective of the study was to determine the ontogeny of P-gp in the human brain.Methods:Postmortem cortex samples from gestational age (GA) 20-26 wk, GA 36-40 wk, postnatal age (PNA) 0-3 mo, PNA 3-6 mo, and adults were immunostained for P-gp.Results:The intensity of P-gp staining in adults was significantly higher compared to at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05). P-gp intensity at GA 20-26 wk (P < 0.05), GA 36-40 wk (P < 0.05), and PNA 0-3 mo (P < 0.05) was significantly lower compared to at PNA 3-6 mo.Conclusion:P-gp expression in the brain is limited at birth, increases with postnatal maturation, and reaches adult levels at ∼3-6 mo of age. Given the immaturity of blood-brain barrier (BBB) P-gp after birth, morphine may concentrate in the brain. This provides mechanistic support to life threatening opioid toxicity seen with maternal codeine use during breastfeeding.

Original languageEnglish
Pages (from-to)417-421
Number of pages5
JournalPediatric Research
Volume78
Issue number4
DOIs
StatePublished - 1 Oct 2015
Externally publishedYes

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