ANALGESIC RESPONSE AND PLASMA AND BRAIN EXTRACELLULAR FLUID PHARMACOKINETICS OF MORPHINE AND MORPHINE-6-BETA-D-GLUCURONIDE IN THE RAT

The analgesic effects of subcutaneously administered morphine and morp hine-6-beta-D-glucuronide (M6G) were determined in male Sprague-Dawley rats. Morphine produced a dose-dependent (2.5 to 10.0 mg/kg) analgesi c response as measured by the tail-flick test. M6G in the same doses a s 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 dia lysis technique and in BECF after administration of the drugs (10.0 mg /kg s.c.). The concentrations of morphine and M6G in BECF were determi ned by using microdialysis. The concentration of M6G in plasma and BEC F at each time interval after its administration was much higher than morphine. The maximal concentrations in plasma and AUC(O-infinity), va lues for M6G were, thus, significantly higher for M6G than for morphin e in plasma and BECF. In BECF, the T-max value for M6G was lower than for morphine, but the t(1/2) (beta) Values did not differ. In plasma, T-max and T-1/2 values for M6G and morphine did not differ, but volume of distribution and total clearance values for M6G were lower than fo r morphine. It is con; eluded that per milligram, M6G has a much highe r analgesic potency than morphine in the rat and these differences may be related, in part, to the higher levels of M6G in comparison to mor phine in plasma and BECF.