Lam Jessica, Baello Stephanie, Iqbal Majid, Kelly Lauren E, Shannon Patrick T, Chitayat David, Matthews Stephen G, Koren Gideon
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.
Pediatr Res. 2015 Oct;78(4):417-21. doi: 10.1038/pr.2015.119. Epub 2015 Jun 18.
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.
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.
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.
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.
与大龄婴儿和成年人相比，新生儿对阿片类药物的中枢抑制作用表现出更高的敏感性。P-糖蛋白（P-gp）发育有限可能会限制新生儿将吗啡从大脑排出回体循环的能力。本研究的目的是确定人脑中P-gp的个体发生情况。
对妊娠龄（GA）20 - 26周、GA 36 - 40周、出生后年龄（PNA）0 - 3个月、PNA 3 - 6个月的尸检皮质样本以及成年人的样本进行P-gp免疫染色。
与GA 20 - 26周（P < 0.05）、GA 36 - 40周（P < 0.05）和PNA 0 - 3个月（P < 0.05）相比，成年人中P-gp染色强度显著更高。与PNA 3 - 6个月相比，GA 20 - 26周（P < 0.05）、GA 36 - 40周（P < 0.05）和PNA 0 - 3个月（P < 0.05）时的P-gp强度显著更低。
大脑中P-gp的表达在出生时受限，随着出生后成熟而增加，并在约3 - 6个月龄时达到成人水平。鉴于出生后血脑屏障（BBB）P-gp不成熟，吗啡可能会在大脑中蓄积。这为母乳喂养期间母亲使用可待因导致的危及生命的阿片类药物毒性提供了机制支持。
