Lack of cross-tolerance on multiple opiate receptors in the mouse vas deferens.
Lack of cross-tolerance on multiple opiate receptors in the mouse vas deferens.
复制标题
小鼠输精管中多种阿片受体缺乏交叉耐受性。
作者：
R. Schulz;M. Wüster;Heinz Krenss;A. Herz
阿片耐受性的发展已经在小鼠输精管中进行了研究，该输精管含有µ-和δ-阿片受体。长期输注选择性作用于µ-或δ-受体的阿片类药物是通过渗透性微泵完成的。对[D-丙氨酸，D-亮氨酸]脑啡肽(DADL)处理的小鼠输精管的体外试验显示，小鼠对δ受体的耐受度是对照组的800倍，而µ受体没有受到影响。因此，观察到对δ受体激动剂如亮氨酸脑啡肽的交叉耐受，但对µ受体激动剂如去甲吗啡没有交叉耐受。另一方面，强效阿片类药物舒芬太尼几乎选择性地作用于µ受体，使对µ受体激动剂有高度的耐受性，但不会改变对δ受体激动剂的敏感性。一些阿片类药物，包括β-内啡肽，在δ受体耐受制剂和µ受体耐受制剂中表现出一定程度的交叉耐受。在使用δ受体激动剂DADL的体外急性耐受的输精管畸形患者中，也获得了基本上相同的结果。用麻醉性拮抗剂纳洛酮挑战高度耐受的血管延缓未显示出任何戒断迹象。在高度耐受的血管发育迟缓症中未能证明依赖可能是由于在阿片受体结合位点水平上慢性阿片类药物暴露的适应过程。结论：阿片受体的选择性耐受形成可以可靠地实现其分化。
The development of opiate tolerance has been studied in the mouse vas deferens, which contains µ- and δ-opiate receptors. Long-term infusion of opioids acting selectively on either µ- or δ-receptors was accomplished by means of osmotic minipumps. In vitro tests of vasa deferentia from chronically [D-Ala2,D-Leu5]enkephalin (DADL)-treated mice revealed an 800-fold degree of tolerance for δ-receptors, while µ-receptors were left unaffected. Accordingly, cross-tolerance to δ-receptor agonists, e.g., leucine-enkephalin, was observed but not to µ-receptor agonists, e.g., normorphine. On the other hand, infusion of the potent opioid sufentanyl, which almost selectively acts at µ-receptors, brings about a high degree of tolerance for µ-receptor agonists, but causes no change in sensitivity to δ-receptor agonists. A number of opioids, including β-endorphin, exhibit some degree of cross-tolerance in δ-receptor-tolerant as well as in µ-receptor-tolerant preparations. Essentially identical results were obtained in vasa deferentia made acutely tolerant in vitro using the δ-receptor agonist DADL. Challenge of highly tolerant vasa deferentia with the narcotic antagonist naloxone failed to demonstrate any withdrawal sign. The failure to demonstrate dependence in highly tolerant vasa deferentia may be due to adaptational processes upon chronic opioid exposure at the opiate receptor binding site level. It is concluded that opiate receptor differentiation can be reliably achieved by means of their selective tolerance development.