Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and...

The analgesic effects of subcutaneously administered morphine and morphine-6-beta-D-glucuronide (M6G) were determined in male Sprague-Dawley rats. Morphine produced a dose-dependent (2.5 to 10.0 mg/kg) analgesic response as measured by the tail-flick test. M6G in the same doses as morphine produced a greater degree of analgesia with longer duration of action. The concentrations of M6G and morphine were determined in plasma as the protein unbound form after the use of an equilibrium dialysis technique and in BECF after administration of the drugs (10.0 mg/kg s.c.). The concentrations of morphine and M6G in BECF were determined by using microdialysis. The concentration of M6G in plasma and BECF at each time interval after its administration was much higher than morphine. The maximal concentrations in plasma and AUC0-infinity values for M6G were, thus, significantly higher for M6G than for morphine in plasma and BECF. In BECF, the Tmax value for M6G was lower than for morphine, but the t1/2 beta values did not differ. In plasma, Tmax and T1/2 values for M6G and morphine did not differ, but volume of distribution and total clearance values for M6G were lower than for morphine. It is concluded that per milligram, M6G has a much higher analgesic potency than morphine in the rat and these differences may be related, in part, to the higher levels of M6G in comparison to morphine in plasma and BECF.