De Vries T J, Tjon Tien Ril G H, Van der Laan J W, Mulder A H, Schoffelmeer A N
Department of Pharmacology, Free University, Medical Faculty, Amsterdam, The Netherlands.
Life Sci. 1993;52(21):1685-93. doi: 10.1016/0024-3205(93)90476-j.
In order to investigate the role of mu-opioid receptor regulation in catecholaminergic neurotransmission during morphine tolerance/dependence and supersensitivity, we measured changes in number and functional properties of two distinct types of mu receptors in the brain of rats chronically treated with morphine and naltrexone. In membranes of striatum and cortex of morphine treated rats the binding of mu ligand [3H]DAMGO was unaltered, whereas an increase in mu binding sites was found in these brain regions of naltrexone treated rats. The ability of the mu agonist DAMGO to inhibit the dopamine D-1 receptor stimulated cAMP production in striatal slices and the electrically evoked release of [3H]noradrenaline from cortical slices was unaffected in both experimental groups. The major changes found were an increased D-1 receptor stimulated cAMP production and an enhanced release of noradrenaline in morphine treated rats and a decreased D-1 receptor stimulated cAMP production in naltrexone treated rats. These data support the hypothesis that tolerance and supersensitivity to morphine and other mu-opioids may be caused by up- and down-regulated neuronal second messenger systems linked to mu-opioid receptors, rather than by changes in the sensitivity of the mu-opioid receptor itself.
为了研究μ-阿片受体调节在吗啡耐受/依赖及超敏反应过程中对儿茶酚胺能神经传递的作用，我们检测了长期接受吗啡和纳曲酮处理的大鼠脑中两种不同类型μ受体的数量及功能特性变化。在吗啡处理大鼠的纹状体和皮质膜中，μ配体[³H]DAMGO的结合未发生改变，而在纳曲酮处理大鼠的这些脑区中发现μ结合位点增加。在两个实验组中，μ激动剂DAMGO抑制纹状体切片中多巴胺D-1受体刺激的cAMP产生以及抑制皮质切片中电诱发的[³H]去甲肾上腺素释放的能力均未受影响。主要发现的变化是，吗啡处理大鼠中D-1受体刺激的cAMP产生增加以及去甲肾上腺素释放增强，而纳曲酮处理大鼠中D-1受体刺激的cAMP产生减少。这些数据支持以下假说：对吗啡及其他μ-阿片类药物的耐受和超敏反应可能是由与μ-阿片受体相关的神经元第二信使系统的上调和下调引起的，而非由μ-阿片受体自身敏感性的变化所致。
