Effects of adrenalectomy on pharmacokinetics and antinociceptive activity of morphine in rats.

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Abstract
The effects of adrenalectomy on the pharmacokinetics and antinociceptive activity of morphine were investigated to elucidate the mechanism of adrenalectomy-induced potentiation of morphine antinociception in rats. Plasma concentrations of morphine were estimated specifically and serially in each rat by high performance liquid chromatography with an electrochemical detector. After the intravenous administration of 10 mg/kg morphine, the plasma half-life of morphine was significantly prolonged by adrenalectomy without any effect on the volume of morphine distribution. After the subcutaneous administration of 7 mg/kg morphine, pharmacokinetic parameters were changed by adrenalectomy in the same manner as after intravenous administration. In contrast, after the subcutaneous injection of 3.5 mg/kg morphine, adrenalectomy failed to change the pharmacokinetic parameters. The antinociceptive potency of subcutaneously administered morphine was enhanced by adrenalectomy for both doses of morphine (3.5 and 7 mg/kg). Morphine antinociception at the dose of 3.5 mg/kg, s.c., in the adrenalectomized group was equipotent with that of 7 mg/kg, s.c., in the sham-operated group, but plasma morphine concentrations for 3.5 mg/kg, s.c., in the adrenalectomized group were significantly lower than those for 7 mg/kg morphine, s.c., in the sham-operated group. These results suggest that the enhancement of morphine antinociception by adrenelectomy can not be explained by the increased morphine level alone.