The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+)mice

1 The aim of this study was to investigate whether blood-brain barrier tran sport of morphine was affected by the absence of mdr1a-encoded P-glycoprote in (Pgp), by comparing mdr1a (-/-) mice with mdr1a (+/+) mice. 2 Mdr1a (-/-) and (+/+) mice received a constant infusion of morphine for 1 , 2 or 4 h (9 nmol/min/mouse). Microdialysis was used to estimate morphine unbound concentrations in brain extracellular fluid during the 4 h infusion . Two methods of estimating in vivo recovery were used: retrodialysis with nalorphine as a calibrator, and the dynamic-no-net-flux method. 3 Retrodialysis loss of morphine and nalorphine was similar in vivo. Unboun d brain extracellular fluid concentration ratios of (-/-)/(+/+) were 2.7 fo r retrodialysis and 3.6 for the dynamic-no-net-flux at 4 h, with correspond ing total brain concentration ratios of (-/-)/(+/+) being 2.3 for retrodial ysis and 2.6 for the dynamic-no-net-flux. The total concentration ratios of brain/plasma were 1.1 and 0.5 for mdr1a (-/-) and (+/+) mice, respectively . 4 No significant differences in the pharmacokinetics of the metabolite morp hine-3-glucoronide were observed between (-/-) and (+/+) mice. 5 In conclusion, comparison between mdr1a (-/-) and (+/+) mice indicates th at Pgp participates in regulating the amount of morphine transport across t he blood-brain barrier.