Arends R H, Hayashi T G, Luger T J, Shen D D
Pain Research, Clinical Research Division, Fred Hutchinson Cancer Research Center, Department of Pharmaceutics, University of Washington, Seattle, Washington 98109-1024, USA.
J Pharmacol Exp Ther. 1998 Aug;286(2):585-92.
As a follow-up study to an earlier report that racemic fenfluramine can acutely potentiate the analgesic effects of morphine in humans, we investigated the effects of fenfluramine on the development of tolerance to morphine analgesia in rats. Antinociceptive effect, as measured by the tail-flick latency, was studied over 8 days in rats that received continuous i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day of fenfluramine, 3) both drugs concomitantly or 4) saline. Infusion with morphine alone resulted in a peak analgesia of 100% maximal possible effect, which declined with time; full tolerance was reached by day 4. Fenfluramine treatment alone had no effect. Fenfluramine coinfusion attenuated the development of tolerance to morphine; >70% maximal possible effect was still present on day 4. The effect of fenfluramine coinfusion occurred in the absence of a significant increase in plasma or brain morphine concentration, or a decrease in the accumulation of morphine's putative antagonistic metabolite, morphine-3-glucuronide. In another set of infusion experiments, rats were challenged with a single i.p. dose of morphine to characterize the morphine dose-response curves at 10 hr following 4-day i.v. infusion of 1) 22 mg/kg/day of morphine, 2) 20 mg/kg/day fenfluramine, 3) morphine plus fenfluramine or 4) saline. An acute i. p. morphine challenge dose response experiment was also conducted in naïve control rats and in rats receiving a concomitant i.p. injection of fenfluramine (2.4 mg/kg). Coinjection of fenfluramine acutely potentiated the antinociceptive potency of morphine. However, potentiation alone does not fully account for the apparent attenuation of tolerance during morphine i.v. infusion. ED50 of morphine was elevated to 7.0 mg/kg in the morphine-infused rats compared to 2.4 mg/kg in saline-infused rats. Coinfusion of fenfluramine increased ED50 to only 3.7 mg/kg. These results demonstrate that fenfluramine significantly attenuates tolerance development to morphine by modulating the pharmacological process responsible for tolerance development to morphine.
作为对先前一份报告（消旋芬氟拉明可急性增强吗啡对人体的镇痛作用）的后续研究，我们调查了芬氟拉明对大鼠吗啡镇痛耐受性形成的影响。通过甩尾潜伏期来衡量的抗伤害感受作用，在接受连续静脉输注的大鼠中进行了为期8天的研究，这些大鼠分别接受：1）22毫克/千克/天的吗啡；2）20毫克/千克/天的芬氟拉明；3）两种药物同时使用；4）生理盐水。单独输注吗啡导致最大可能效应的峰值镇痛率为100%，且随时间下降；到第4天达到完全耐受。单独使用芬氟拉明治疗没有效果。同时输注芬氟拉明减弱了对吗啡耐受性的形成；在第4天仍存在>70%的最大可能效应。同时输注芬氟拉明的效果在血浆或脑吗啡浓度没有显著增加，或吗啡假定的拮抗代谢物吗啡-3-葡糖醛酸的蓄积没有减少的情况下出现。在另一组输注实验中，大鼠接受单次腹腔注射吗啡，以描绘在静脉输注4天（分别为1）22毫克/千克/天的吗啡；2）20毫克/千克/天的芬氟拉明；3）吗啡加芬氟拉明；4）生理盐水）后10小时的吗啡剂量-反应曲线。还在未处理的对照大鼠和接受腹腔注射芬氟拉明（2.4毫克/千克）的大鼠中进行了急性腹腔注射吗啡挑战剂量反应实验。同时注射芬氟拉明显著增强了吗啡的抗伤害感受效力。然而，仅增强作用并不能完全解释静脉输注吗啡期间耐受性的明显减弱。与生理盐水输注的大鼠中2.4毫克/千克相比，吗啡输注的大鼠中吗啡的半数有效剂量（ED50）升高到7.0毫克/千克。同时输注芬氟拉明仅将ED50增加到3.7毫克/千克。这些结果表明，芬氟拉明通过调节负责吗啡耐受性形成的药理过程，显著减弱了对吗啡耐受性的形成。
