Substance related disorders in pregnancy constitute a public health problem with increased risk of maternal and neonatal morbidity and mortality. Reinforcement from drugs of abuse is related to the rate of onset of action and route of administration. An exploratory project is proposed to test a novel strategy that the rate and amount of morphine reaching the maternal brain and the developing fetuses can be reduced by using St Johns wort (SJW), a natural product, to increase the activity of efflux drug transporters located in the blood brain barrier and placenta. The research will use pregnant Sprague-Dawley rats as a model for pregnancy. Morphine is a substrate of the ABCB1 gene product, P-glycoprotein (P-gp), that we have shown in preliminary data can be induced by SJW. Pharmacokinetic studies will be performed to compare the rate and amount of morphine, administered either orally or intravenously, reaching various tissues in animals pre-treated with SJW for fourteen days compared to animals treated with vehicle. Changes in drug exposure to fetal brain, whole fetus, maternal brain, and other tissues will be correlated with changes in mRNA and protein expression in corresponding tissues to confirm whether changes in gene transcription, or translation, correspond to changes in drug exposure. Using up-regulation of drug transporter activity to simultaneously minimize maternal and fetal exposure to an opioid is a novel approach to treatment of the pregnant addict that has not been previously investigated, to our knowledge. Successful completion of this exploratory project could provide a foundation of pre-clinical data from which to launch an entirely new approach to treatment of addiction during pregnancy.
This preclinical study will determine if the amount of morphine that reaches the maternal brain and developing fetus in pregnant Sprague-Dawley rats can be minimized with the use of a natural product to increase the activity of efflux drug transporters located in the blood brain barrier and the placenta. The results will be a test of a novel pharmacological strategy for treatment of pregnant women with opioid dependence/addiction.
