Acute tolerance in morphine analgesia: continuous infusion and single injection in rats

This study aimed to determine whether the decline of the analgesic effect of morphine with a continuous infusion or that after a single injection correlates with the changes in brain concentration of morphine. The analgesic effect of morphine and its brain and serum concentrations were determined with a continuous 8-h infusion at a constant rate and after a single subcutaneous injection of the agent. The analgesic effect was determined by measuring the threshold of motor response to noxious stimulation. Brain and serum concentrations of morphine were detected by radioimmunoassay with the use of 125I-labeled morphine. With the constant-rate (4 mg.kg-1.h-1, intravenous) morphine infusion, the peak of analgesia could not be maintained: the increase in the pain threshold at 2 h was 1,003 g and at 8h was 286 g (a decrease in analgesia by 72%, P less than 0.0002). At the same time, the brain morphine concentration tended to increase, to 278 ng/g at 2 h and 329 ng/g at 8 h. After the single morphine injection (6 mg/kg, subcutaneous), recovery from analgesia occurred at a much faster rate than did the decrease in morphine brain concentration; the decrease in pain threshold was 79% at 90 vs. 30 min after the injection (P less than 0.0001), and the corresponding decrease in brain concentration was 28% (NS). The absence of correlation between analgesia and morphine brain concentration both with the constant-rate morphine infusion and after the single injection suggests the development of acute tolerance, which is pharmacodynamic in nature.