THE ONTOGENY OF P-GLYCOPROTEIN IN THE DEVELOPING HUMAN BLOOD BRAIN BARRIER: IMPLICATION FOR OPIOID TOXICITY IN NEONATES

Abstract

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), located on the luminal membrane of the brain endothelial cells, may limit the ability of the neonate to efflux morphine from the brain back to the systemic circulation. Presently, little is known about blood brain barrier P-gp expression during human development. The objective of the study was to determine the ontogeny of P-gp in the human BBB. Postmortem cortex samples from gestational age (GA) 20–26 weeks, GA 36–40 weeks, postnatal age (PNA) 0–3 months, PNA 3–6 months, and adults were immunostained for P-gp. Analysis was carried out by spinning disc confocal microscopy. The intensity of P-gp staining in adults was significantly higher compared to at GA 20–26 weeks (p=0.0002), GA 36–40 weeks (p=0.0002), and PNA 0–3 months (p=0.0044). P-gp intensity at GA 20–26 weeks (p=0.0011), GA 36–40 weeks (p=0.0013), and PNA 0–3 months (p=0.0173) was significantly lower compared to at PNA 3–6 months. P-gp expression in the BBB is limited at birth, increases with postnatal maturation, and reaches adult levels at approximately 3–6 months of age. Given the immaturity of 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.