吗啡预处理增强小鼠体内纳洛酮向脑内的分布。

Enhanced naloxone distribution to the brain by morphine pretreatment in mice.

作者信息

Lange D G, Fujimoto J M, Roerig S, Wang R I

出版信息

Drug Metab Dispos. 1977 Mar-Apr;5(2):167-73.

Abstract

An increase in the disposition of naloxone to the mouse brain was observed for animals previously exposed to morphine. Compared to controls, mice receiving morphine sulfate (10 mg/kg, sc) 3 hr prior to naloxone had a 28% increase in naloxone concentration in brain (200 to 260 pmol of naloxone per g of brain) 10 min after 3H-naloxone-HCl (0.4 mg/kg, 11.0 micronCi/kg, sc) administration. Also, if similar morphine-pretreated mice received a second dose of morphine sulfate (1.0 mg/kg, sc) concurrent with 3H-naloxone-HCl, the morphine-induced enhancement of 3H-naloxone concentration in brain was unaltered. This drug-treatment protocol paralleled that used by others in pA2-analgesia assays to demonstrate sensitization to naloxone for morphine-pretreated animals. In prior (3 hr) morphine-treated animals, administration of 3H-naloxone-HCl (0.1 mg/kg, 33.3 micronCi/kg) iv resulted in an 11.0% increase in 3H-naloxone brain concentration after 1 min. Thus, the enhancement of naloxone brain concentration was independent of the route of naloxone administration. No enhancement of 3H-naloxone brain concentration could be seen 24 hr after morphine sulfate pretreatment (10 mg/kg, sc), a decline in the effect similar to that seen for morphine-induced sensitization to naloxone. Finally, when morphine pellet-implanted mice (75 mg of morphine base, 72 hr) were administered 3H-naloxone-HCl (0.4 mg/kg, 10.0 micronCi/kg, sc), only a 22.5% enhancement of 3H-naloxone concentration in brain was obtained, as opposed to a reported 8-fold increase in the potency of naloxone. Thus, although a number of similarities exist between the enhancement by morphine of naloxone concentration in brain and its sensitization to the antagonistic activity of naloxone, a quantitative correlation appears to be lacking between the two phenomena.

摘要

对于先前接触过吗啡的动物，观察到纳洛酮向小鼠脑内的分布增加。与对照组相比，在给予盐酸³H-纳洛酮（0.4 mg/kg，11.0 μCi/kg，皮下注射）10分钟后，在纳洛酮给药前3小时接受硫酸吗啡（10 mg/kg，皮下注射）的小鼠脑内纳洛酮浓度增加了28%（从每克脑200皮摩尔纳洛酮增加到260皮摩尔纳洛酮）。此外，如果类似的经吗啡预处理的小鼠在给予盐酸³H-纳洛酮的同时接受第二剂硫酸吗啡（1.0 mg/kg，皮下注射），吗啡诱导的脑内³H-纳洛酮浓度升高并未改变。这种药物处理方案与其他人在pA2镇痛试验中用于证明吗啡预处理动物对纳洛酮敏感化的方案相似。在先前（3小时）经吗啡处理的动物中，静脉注射盐酸³H-纳洛酮（0.1 mg/kg，33.3 μCi/kg）1分钟后，³H-纳洛酮脑浓度增加了11.0%。因此，纳洛酮脑浓度的升高与纳洛酮的给药途径无关。在硫酸吗啡预处理（10 mg/kg，皮下注射）24小时后，未观察到³H-纳洛酮脑浓度的升高，这种效应的下降类似于吗啡诱导的对纳洛酮敏感化所观察到的情况。最后，当给植入吗啡丸的小鼠（75 mg吗啡碱，72小时）给予盐酸³H-纳洛酮（0.4 mg/kg，10.0 μCi/kg，皮下注射）时，仅观察到脑内³H-纳洛酮浓度升高了22.5%，而不是报道的纳洛酮效力增加8倍。因此，尽管吗啡对脑内纳洛酮浓度的升高及其对纳洛酮拮抗活性的敏感化之间存在许多相似之处，但这两种现象之间似乎缺乏定量相关性。