TY - JOUR
T1 - The ontogeny of P-glycoprotein in the developing human blood-brain barrier
T2 - Implication for opioid toxicity in neonates
AU - Lam, Jessica
AU - Baello, Stephanie
AU - Iqbal, Majid
AU - Kelly, Lauren E.
AU - Shannon, Patrick T.
AU - Chitayat, David
AU - Matthews, Stephen G.
AU - Koren, Gideon
N1 - Publisher Copyright:
© 2015 International Pediatric Research Foundation, Inc.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84942882777&partnerID=8YFLogxK
U2 - 10.1038/pr.2015.119
DO - 10.1038/pr.2015.119
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C2 - 26086643
AN - SCOPUS:84942882777
SN - 0031-3998
VL - 78
SP - 417
EP - 421
JO - Pediatric Research
JF - Pediatric Research
IS - 4
ER -