Ritzmann R F, Walter R, Bhargava H N, Flexner L B
Proc Natl Acad Sci U S A. 1979 Nov;76(11):5997-8. doi: 10.1073/pnas.76.11.5997.
We have previously reported that the administration of cyclo(Leu-Gly) to mice prior to morphinization blocked the development of tolerance to the analgesic effects of morphine as well as the development of some signs of physical dependence. In the present series of experiments, the effect of the same peptide treatment on changes in dopamine receptor sensitivity induced by chronic morphine treatment were determined. Changes in dopamine receptor sensitivity were determined by measuring (i) the effect of the dopamine agonist apomorphine on locomotor activity and (ii) the hypothermic response to another dopamine agonist, piribedil. Mice that had received the chronic morphine treatment were found to require significantly less apomorphine to produce an increase in locomotor activity, and they exhibited a significantly greater hypothermic response to piribedil than did morphine-naive mice. The injection of 0.2 mumol of cyclo(Leu-Gly) per mouse 2 hr prio to morphine treatment prevented this increased response to both dopamine agonists. Administration of the peptide after the tolerance and dependence had developed did not alter morphine tolerant and dependent states states or the enhanced response to apomorphine or piribedil. It is concluded that dopamine receptor supersensitivity may be involved in the development of narcotic tolerance and physical dependence.
我们之前曾报道，在给小鼠注射吗啡之前给予环（亮氨酸-甘氨酸）可阻断对吗啡镇痛作用耐受性的发展以及一些身体依赖性体征的出现。在本系列实验中，确定了相同肽处理对慢性吗啡处理诱导的多巴胺受体敏感性变化的影响。通过测量（i）多巴胺激动剂阿扑吗啡对运动活性的影响以及（ii）对另一种多巴胺激动剂匹莫齐特的体温过低反应来确定多巴胺受体敏感性的变化。发现接受慢性吗啡处理的小鼠产生运动活性增加所需的阿扑吗啡量显著减少，并且它们对匹莫齐特的体温过低反应比未接触过吗啡的小鼠显著更大。在吗啡处理前2小时每只小鼠注射0.2 μmol环（亮氨酸-甘氨酸）可防止对两种多巴胺激动剂的这种反应增强。在耐受性和依赖性形成后给予该肽不会改变吗啡耐受和依赖状态或对阿扑吗啡或匹莫齐特的增强反应。得出的结论是，多巴胺受体超敏反应可能参与了麻醉耐受性和身体依赖性的发展。
