The effect of cumulative dosing on the analgesic potency of morphine in mice.

Opioid analgesic potency can be evaluated using cumulative dosing, in which subjects are repeatedly administered a drug and tested after each dose until a criterion effect is reached. Although many laboratories use cumulative dosing, the effects of varying the starting dose and the magnitude of the increment dose on morphine analgesia (tail flick) in mice have not been evaluated. In experiment 1. mice were injected with the same starting dose [0.5 mg/kg subcutaneously (SC)] and 30 min later were tested for analgesia. Mice that were not analgesic were administered an increment dose (0.5, 1.0, 2.0, 2.5, or 3.0 mg/kg) and retested. The process was continued until all mice were analgesic. There was a significant effect of increment dose on morphine potency, with the relative potency increasing as the increment dose was increased. In experiment 2, different starting doses (0.5, 1.0, 2.0, or 3.0 mg/kg) were used with a constant increment dose of 1.0 mg/kg. There was a significant effect of starting dose on the potency of morphine, with the relative potency increasing as the starting dose increased. To determine if increment and starting dose affect tolerance estimates, mice were implanted SC with a 25- or 75-mg morphine or placebo pellet for 7 days and then tested using cumulative dose-response. Changes in the increment dose significantly affected the degree of tolerance for mice implanted with a 25-mg morphine pellet but not for mice implanted with a 75-mg morphine pellet. Changes in the starting dose did not significantly alter estimates of tolerance. Overall, these data indicate that the starting dose and increment dose can impact on morphine's potency determined by cumulative dosing protocols. Furthermore, estimates of tolerance can be affected by dosing parameters in the cumulative dosing protocol. These results suggest that cumulative dosing procedures should be standardized across experiments.