DIRECT CORRELATION BETWEEN LEVEL OF MORPHINE AND ITS BIOCHEMICAL EFFECT ON MONOAMINE SYSTEMS IN MOUSE-BRAIN - EVIDENCE FOR INVOLVEMENT OF DOPAMINERGIC-NEURONS IN THE PHARMACOLOGICAL ACTION OF ACUTE MORPHINE
DIRECT CORRELATION BETWEEN LEVEL OF MORPHINE AND ITS BIOCHEMICAL EFFECT ON MONOAMINE SYSTEMS IN MOUSE-BRAIN - EVIDENCE FOR INVOLVEMENT OF DOPAMINERGIC-NEURONS IN THE PHARMACOLOGICAL ACTION OF ACUTE MORPHINE
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DOI：
10.1016/0006-2952(83)90468-9
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发表时间：
1983-01-01
影响因子：
5.8
通讯作者：
MCGAUGH, JL
中科院分区：
文献类型：
--
作者：
ISHIKAWA, K;SHIBANOKI, S;MCGAUGH, JL
吗啡是一种重要的药物，作为一种实验工具，用于研究疼痛和药物依赖性，因为它的药理学和毒理学作用包括镇痛作用和依赖性。同时研究了吗啡在CNS中的药代动力学（摄取和消除）和药效学（对单胺系统的生化作用）。给体重约25 g的ICR小鼠静脉注射几个剂量（2.5-80 mg/kg）的吗啡。分别于注射后10、30 min、1、2、4、8、24 h用微波照射（5 kW，0.6 s）处死动物。脑内吗啡和代谢相关物质（包括单胺[去甲肾上腺素（去甲肾上腺素）、多巴胺（DA）、5-羟色胺（5-HT）、3，4-二羟基苯乙酸（DOPAC）、3-甲氧基-4-羟基苯乙酸（高香草酸，HVA）、5-羟基吲哚乙酸（5-HIAA）、酪氨酸和色氨酸]通过有机萃取和高效液相色谱与电化学检测的组合在相同的样品中测定。吗啡的脑内水平依赖于注射剂量，药物的生物半衰期估计为约1小时。注射吗啡（2.5-80 mg/kg）导致单胺代谢物显著增加，尽管母体递质浓度仅发生轻微变化。脑内吗啡浓度与DOPAC/DA和HVA/DA比值呈显著正相关（r分别为0.7033和0.6455，P <0.0001）。吗啡水平与5-HIAA/5-HT的相关性低于DOPAC/DA和HVA/DA。单胺系统尤其是DA与吗啡的生物化学效应密切相关。所提出的程序是有用的，作为一种新的方法，在生化药理学，其中药物的分布（药代动力学）和药物的生化效应（药效学）之间的直接相关性可以测量。
Morphine is an important drug, as an experimental tool, for investigating pain and drug dependence since its pharmacological and toxicological effects include an analgesic action and dependence. The pharmacokinetics (uptake and elimination) and pharmacodynamics (biochemical effects on monoamine systems) of morphine in the CNS were investigated concurrently. ICR mice, weighing about 25 g, were injected i.v. with several doses (2.5-80 mg/kg) of morphine. The animals were killed by microwave irradiation (5 kW, 0.6 s) at 10 and 30 min, and 1, 2, 4, 8 and 24 h after the injection. The intracerebral levels of morphine and metabolically related substances consisting of monoamines [noradrenaline (norepinephrine), dopamine (DA), 5-hydroxytryptamine (5-HT), 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA), 5-hydroxyindoleacetic acid (5-HIAA), tyrosine and tryptophan] were determined in identical samples by a combination of organic extraction and high-performance liquid chromatography with electrochemical detection. The intracerebral level of morphine depended on the dose injected, and the biological half-life of the drug was estimated to be about 1 h. The morphine injection (2.5-80 mg/kg) caused significant increases in monoamine metabolites, although only slight changes occurred in the concns [concentrations] of parent transmitters. The intracerebral level of morphine was significantly correlated with the ratios DOPAC/DA and HVA/DA (r = 0.7033, P < 0.0001; and r = 0.6455, P < 0.0001, respectively). The correlation between the morphine level and 5-HIAA/5-HT was lower than those for DOPAC/DA and HVA/DA. Monoamine systems, especially DA, are apparently closely involved in the biochemical effects of morphine. The proposed procedure is useful as a new approach in biochemical pharmacology, where the direct correlation between the distribution of a drug (pharmacokinetics) and the biochemical effects of the drug (pharmacodynamics) can be measured.