title: The ontogeny of P-glycoprotein in the developing human blood-brain barrier: implication for opioid toxicity in neonates.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.|Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: Lam
authors.affiliation: Department of Physiology, Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Baello
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Majid
authors.initials: M
authors.lastname: Iqbal
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, Toronto, Ontario, Canada.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Kelly
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Shannon
authors.affiliation: Department of Obstetrics and Gynaecology, Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, Canada.|Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: Department of Physiology, Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Matthews
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.|Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Physiology and Pharmacology, University of Western Ontario, Toronto, Ontario, Canada.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000032:analysis; D000328:Adult; D000367:Age Factors; D000701:Analgesics, Opioid / Q000378:metabolism / Q000633:toxicity*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000737:chemistry* / Q000196:embryology; D002199:Capillary Permeability; D002657:Child Development; D005260:Female; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009020:Morphine / Q000378:metabolism / Q000633:toxicity*; D012307:Risk Factors
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000701:Analgesics, Opioid; D009020:Morphine