Tokuyama S, Ho I K
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson 39216-4505, USA.
Psychopharmacology (Berl). 1996 May;125(2):135-40. doi: 10.1007/BF02249412.
The effects of diltiazem, an L-type Ca2+ channel blocker, on naloxone (an opioid receptor antagonist)-precipitated withdrawal signs and changes in extracellular levels of dopamine (DA) and its metabolites in various brain regions of morphine (a mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa mixed opioid receptor agonist) dependent rats were investigated using high performance liquid chromatography fitted with an electrochemical detector (HPLC-ED). Rats were rendered opioid-dependent by continuous intracerebroventricular (i.c.v.) infusion with morphine (26 nmol/microliters per h) or butorphanol (26 nmol/microliters per h) for 3 days. The expression of physical dependence produced by these opioids, as evaluated by naloxone (5 mg/kg. i.p.)-precipitated withdrawal signs, was reduced by concomitant infusion of diltiazem (10 and 100 nmol/microliters per h). Under the same condition, naloxone decreased the levels of: DA in the cortex, striatum, and midbrain; 3,4-dihydroxyphenylacetic acid (DOPAC) in the cortex, striatum, limbic areas, and midbrain: and homovanilic acid (HVA) in the striatum, limbic areas, and midbrain regions. In animals rendered dependent on butorphanol, the results obtained were similar to those of morphine-dependent rats except for the changes in DOPAC levels. Furthermore, concomitant infusion of diltiazem and opioids blocked the decreases in levels of DA, DOPAC, and HVA in a dose-dependent manner. These results suggest that the augmentation of intracellular Ca2+ mediated through L-type Ca2+ channels during continuous opioid infusion results in a decrease in extracellular levels of DA and its metabolites in some specific regions, which are intimately involved in the expression of withdrawal syndrome precipitated by naloxone.
使用配备电化学检测器的高效液相色谱法（HPLC-ED），研究了L型钙通道阻滞剂地尔硫䓬对纳洛酮（一种阿片受体拮抗剂）诱发的戒断症状以及吗啡（一种μ阿片受体激动剂）或布托啡诺（一种μ/δ/κ混合阿片受体激动剂）依赖大鼠不同脑区细胞外多巴胺（DA）及其代谢产物水平变化的影响。通过连续脑室内（i.c.v.）输注吗啡（每小时26 nmol/微升）或布托啡诺（每小时26 nmol/微升）3天，使大鼠产生阿片依赖。通过纳洛酮（5 mg/kg，腹腔注射）诱发的戒断症状评估，这些阿片类药物产生的身体依赖性表达，因同时输注地尔硫䓬（每小时10和100 nmol/微升）而降低。在相同条件下，纳洛酮降低了以下物质的水平：皮质、纹状体和中脑中的DA；皮质、纹状体、边缘区域和中脑中的3,4-二羟基苯乙酸（DOPAC）；以及纹状体、边缘区域和中脑区域中的高香草酸（HVA）。在依赖布托啡诺的动物中，除了DOPAC水平的变化外，获得的结果与吗啡依赖大鼠相似。此外，同时输注地尔硫䓬和阿片类药物以剂量依赖的方式阻止了DA、DOPAC和HVA水平的降低。这些结果表明，在连续输注阿片类药物期间，通过L型钙通道介导的细胞内Ca2+增加导致某些特定区域细胞外DA及其代谢产物水平降低，这些区域与纳洛酮诱发的戒断综合征的表达密切相关。
