Pharmacokinetic-pharmacodynamic modelling of morphine transport across theblood-brain barrier as a cause of the antinociceptive effect delay in rats- A microdialysis study

Purpose. To quantify the contribution of distributional processes across th e blood-brain barrier (BBB) to the delay in antinociceptive effect of morph ine in rats. Methods. Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arteria l blood by regular sampling. Retrodialysis by drug was used for in vivo cal ibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 mi n intravenously. Nociception, measured by the electrical stimulation vocali sation method, and brood gas status were determined. Results. The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p < 0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28 +/- 0.09 and 0.22 +/- 0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine acros s the BBB. The concentration-effect relationship exhibited a clear hysteris is with an effect delay half-life of 32 and 5 min based on arterial blood a nd brain ECF concentrations, respectively. Conclusions. Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remai ning effect delay of 5 min.