Concentration-effect relationships of morphine and morphine-6 beta-glucuronide in the rat.

1. The aims of the present study were to determine the relationship between the antinociceptive effect and concentrations of morphine and morphine-6 beta-glucuronide (M6G) in plasma and in the brain. 2. Morphine (14.0 and 28.0 mumol/kg) or M6G (8.67 and 17.3 mumol/kg) were administered s.c. to male Hooded-Wistar rats. The antinociceptive effect was measured by the thermal tail-flick method at various times up to 2 h and concentrations of morphine, morphine-3 beta-glucuronide (M3G) and M6G in plasma and in the brain were determined. 3. With a two-fold increment in morphine dose, the areas under the antinociceptive effect-, plasma morphine concentration- and brain morphine concentration-time curves increased by 1.9-, 2.3- and 2.3-fold, respectively. The area under the plasma M3G concentration-time curve increased 2.7-fold. Morphine-6 beta-glucuronide was not detected in any sample. For M6G, doubling of the dose led to a 1.7-fold increase in the area under the curve for plasma-time M6G concentrations but an 8.7-fold increase in the area under the curve for the antinociception-time effect. Concentrations of M6G in the brain were below the limit of quantification. The relationship between antinociceptive effect and plasma morphine or M6G were characterized by counter-clockwise hysteresis loops, probably reflecting a delay in crossing the blood-brain barrier. 4. Morphine-6 beta-glucuronide was approximately equipotent to morphine on the basis of dose, but substantially more potent on the basis of brain concentration.