Wu H E, Hung K C, Mizoguchi H, Fujimoto J M, Tseng L F
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
J Pharmacol Exp Ther. 2001 Dec;299(3):1120-5.
Development of tolerance in mice pretreated intracerebroventricularly with mu-opioid receptor agonist endomorphin-1, endomorphin-2, or [D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-enkephalin (DAMGO) was compared between endomorphin-1- and endomorphin-2-induced antinociception with the tail-flick test. A 2-h pretreatment with endomorphin-1 (30 nmol) produced a 3-fold shift to the right in the dose-response curve for endomorphin-1. Similarly, a 1-h pretreatment with endomorphin-2 (70 nmol) caused a 3.9-fold shift to the right for endomorphin-2. In cross-tolerance experiments, pretreatment with endomorphin-2 (70 nmol) caused a 2.3-fold shift of the dose-response curve for endomorphin-1, whereas pretreatment with endomorphin-1 (30 nmol) caused no change of the endomorphin-2 dose-response curve. Thus, mice acutely tolerant to endomorphin-1 were not cross-tolerant to endomorphin-2, although mice made tolerant to endomorphin-2 were partially cross-tolerant to endomorphin-1; an asymmetric cross-tolerance occurred. Pretreatment with DAMGO 3 h before intracerebroventricular injection of endomorphin-1, endomorphin-2, or DAMGO attenuated markedly the antinociception induced by endomorphin-1 and DAMGO but not endomorphin-2. It is proposed that two separate subtypes of mu-opioid receptors are involved in antinociceptive effects induced by endomorphin-1 and endomorphin-2. One subtype of opioid mu-receptors is stimulated by DAMGO, endomorphin-1, and endomorphin-2, and another subtype of mu-opioid receptors is stimulated solely by endomorphin-2.
通过甩尾试验比较了经脑室内预注射μ-阿片受体激动剂内吗啡肽-1、内吗啡肽-2或[D-Ala(2),N-Me-Phe(4),Gly-ol(5)]-脑啡肽（DAMGO）预处理的小鼠对内吗啡肽-1和内吗啡肽-2诱导的镇痛作用产生耐受性的情况。用内吗啡肽-1（30 nmol）进行2小时预处理后，内吗啡肽-1的剂量-反应曲线向右移动了3倍。同样，用内吗啡肽-2（70 nmol）进行1小时预处理后，内吗啡肽-2的剂量-反应曲线向右移动了3.9倍。在交叉耐受性实验中，用内吗啡肽-2（70 nmol）预处理导致内吗啡肽-1的剂量-反应曲线向右移动2.3倍，而用内吗啡肽-1（30 nmol）预处理对内吗啡肽-2的剂量-反应曲线无影响。因此，急性耐受内吗啡肽-1的小鼠对内吗啡肽-2无交叉耐受性，尽管耐受内吗啡肽-2的小鼠对内吗啡肽-1有部分交叉耐受性；出现了不对称交叉耐受性。在脑室内注射内吗啡肽-1、内吗啡肽-2或DAMGO前3小时用DAMGO预处理，可显著减弱内吗啡肽-1和DAMGO诱导的镇痛作用，但对内吗啡肽-2诱导的镇痛作用无影响。有人提出，内吗啡肽-1和内吗啡肽-2诱导的镇痛作用涉及两种不同的μ-阿片受体亚型。一种阿片μ-受体亚型可被DAMGO、内吗啡肽-1和内吗啡肽-2激活，而另一种μ-阿片受体亚型仅可被内吗啡肽-2激活。
