The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats

Abstract

In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3-glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812±0.034 for M6G alone, 0.0824±0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats.