CONCENTRATION‐EFFECT RELATIONSHIPS OF MORPHINE AND MORPHINE‐6β‐GLUCURONIDE IN THE RAT

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Abstract
SUMMARY: 1. The aims of the present study were to determine the relationship between the antinociceptive effect and concentrations of morphine and morphine‐6β‐glucuronide (M6G) in plasma and in the brain.2. Morphine (14.0 and 28.0 μ‐mol/kg) or M6G (8.67 and 17.3 μmol/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‐3β‐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‐6β‐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 counterclockwise hysteresis loops, probably reflecting a delay in crossing the blood‐brain barrier.4. Morphine‐6β‐glucuronide was approximately equipotent to morphine on the basis of dose, but substantially more potent on the basis of brain concentration.