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 eac h dose until a criterion effect is reached. Although many laboratories use cumulative dosing, the effects of varying the starting dose and t he magnitude of the increment dose on morphine analgesia (tail nick) i n mice have not been evaluated. In experiment 1, mice were injected wi th the same starting dose [0.5 mg/kg subcutaneously (SC)] and 30 min l ater were tested for analgesia. Mice that were not analgesic were admi nistered an increment dose (0.5, 1.0, 2.0, 2.5, or 3.0 mg/kg) and rete sted. The process was continued until all mice were analgesic. There w as a significant effect of increment dose on morphine potency, with th e 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) w ere used with a constant increment dose of 1.0 mg/kg. There was a sign ificant effect of starting dose on the potency of morphine, with the r elative potency;increasing as the starting dose increased. To determin e if increment and starting dose affect tolerance estimates, mice were implanted SC with a 25- or 75-mg morphine or placebo pellet for 7 day s and then tested using cumulative dose-response. Changes in the incre ment dose significantly affected the degree of tolerance for mice impl anted with a 25-mg morphine pellet but not for mice implanted with a 7 5-mg morphine pellet. Changes in the starting dose did not significant ly alter estimates of tolerance. Overall, these data indicate that the starting dose and increment dose can impact on morphine's potency det ermined by cumulative dosing protocols. Furthermore, estimates of tole rance can be affected by dosing parameters in the cumulative dosing pr otocol. These results suggest that cumulative dosing procedures should be standardized across experiments. (C) 1997 Elsevier Science Inc.