Plomp G J, Maes R A, van Ree J M
J Pharmacol Exp Ther. 1981 Apr;217(1):181-8.
The levels of morphine in plasma and brain subcortex of rats were determined by gas-liquid chromatography and radioimmunoassay at various time intervals after a single i.v. injection of graded doses of morphine (0.44, 1.04 and 2.25 mg/kg). The disappearance curve of morphine plasma levels appeared to be composed of at least two exponential terms: a rapid disappearance during the 1st hr, which was dependent on the unit dose of morphine injected and a slower disappearance rate after the 1st hr. The highest morphine levels in the brain were measured already 5 min after its injection and these levels only slightly decreased over the next 2 hr. Thereafter a more rapid disappearance of brain morphine was observed. The brain/plasma ratio gradually increased from 0.18 at 5 min after injection to about 1.0 at 60 and 120 min and decreased to approximately 0.4 at 4 hr after injection. This may suggest that morphine is retained in the brain during the 1st hr after injection and that it might be removed from the brain between 2 and 4 hr, possibly by an active process. The relationship between brain morphine levels and the degree of antinociception as assessed with the hot plate procedure appeared to be rather complicated. Shortly after morphine injection, but also at 60 and 120 min after injection, the antinociceptive effect was much lower than might be expected from the levels of morphine in the brain. Several possible explanations for this phenomenon are discussed. A high dose of naltrexone, which completely blocked the antinociceptive effect of morphine, did not affect brain and plasma levels of morphine. Rifampicin, which attenuates development of morphine tolerance, increased brain levels of morphine but did not change plasma levels. Pretreatment with the tripeptide prolyl-leucyl-glycinamide, which facilitates development of morphine tolerance, decreased brain morphine levels and increased plasma levels at 3 hr after morphine injection. This suggests that tolerance development and the rate with which morphine is removed from the brain may have at least some common underlying mechanisms.
在大鼠单次静脉注射不同剂量（0.44、1.04和2.25mg/kg）吗啡后的不同时间间隔，通过气液色谱法和放射免疫分析法测定血浆和脑皮质下的吗啡水平。吗啡血浆水平的消失曲线似乎由至少两个指数项组成：第1小时内快速消失，这取决于注射的吗啡单位剂量，1小时后消失速率较慢。注射后5分钟时测得脑中吗啡水平最高，在接下来的2小时内这些水平仅略有下降。此后观察到脑吗啡消失更快。脑/血浆比值从注射后5分钟时的0.18逐渐增加到60和120分钟时的约1.0，并在注射后4小时降至约0.4。这可能表明吗啡在注射后第1小时内在脑中潴留，并且可能在2至4小时之间从脑中清除，可能是通过一个主动过程。用热板法评估时，脑吗啡水平与抗伤害感受程度之间的关系似乎相当复杂。吗啡注射后不久，但在注射后60和120分钟时，抗伤害感受作用也远低于根据脑中吗啡水平所预期的程度。讨论了对此现象的几种可能解释。高剂量纳曲酮完全阻断了吗啡的抗伤害感受作用，但不影响吗啡的脑和血浆水平。利福平可减弱吗啡耐受性的发展，它增加了脑吗啡水平，但未改变血浆水平。用促进吗啡耐受性发展的三肽脯氨酰 - 亮氨酰 - 甘氨酰胺预处理，在吗啡注射后3小时降低了脑吗啡水平并增加了血浆水平。这表明耐受性的发展以及吗啡从脑中清除的速率可能至少有一些共同的潜在机制。
