Duttaroy A, Kirtman R, Farrell F, Phillips M, Philippe J, Monderson T, Yoburn B C
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
Pharmacol Biochem Behav. 1997 Sep;58(1):67-71. doi: 10.1016/s0091-3057(96)00463-7.
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.
阿片类镇痛药的效力可以通过累积给药来评估，即对受试者反复给予药物，并在每次给药后进行测试，直到达到标准效应。尽管许多实验室都采用累积给药，但起始剂量和增量剂量的变化对小鼠吗啡镇痛作用（甩尾）的影响尚未得到评估。在实验1中，给小鼠皮下注射相同的起始剂量[0.5毫克/千克]，30分钟后测试镇痛效果。未产生镇痛作用的小鼠给予增量剂量（0.5、1.0、2.0、2.5或3.0毫克/千克）并再次测试。该过程持续进行，直到所有小鼠都产生镇痛作用。增量剂量对吗啡效力有显著影响，随着增量剂量增加，相对效力也增加。在实验2中，使用不同的起始剂量（0.5、1.0、2.0或3.0毫克/千克），增量剂量恒定为1.0毫克/千克。起始剂量对吗啡效力有显著影响，随着起始剂量增加，相对效力也增加。为了确定增量剂量和起始剂量是否影响耐受性评估，给小鼠皮下植入25毫克或75毫克吗啡或安慰剂丸剂7天，然后使用累积剂量反应进行测试。增量剂量的变化对植入25毫克吗啡丸剂的小鼠的耐受程度有显著影响，但对植入75毫克吗啡丸剂的小鼠没有影响。起始剂量的变化并未显著改变耐受性评估。总体而言，这些数据表明起始剂量和增量剂量可影响通过累积给药方案确定的吗啡效力。此外，累积给药方案中的给药参数可影响耐受性评估。这些结果表明，累积给药程序应在各实验中实现标准化。
