Garaulet J V, Laorden M L, Milanés M V
Department of Physiology and Pharmacology, University School of Medicine, Murcia, Spain.
J Pharmacol Exp Ther. 1994 Jun;269(3):993-9.
The present investigation was aimed at elucidating if chronic activation of mu opioid receptor induces development of tolerance to mu (specific tolerance) and kappa agonists (cross-tolerance) in the guinea pig ileum myenteric plexus-longitudinal muscle strip. Morphine (prototype of mu agonist), [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO) and sufentanil (selective mu-agonists) and U-50,488H (selective kappa agonist) were selected. Tolerance to morphine was induced by subcutaneous implantation of morphine pellets (75 mg per pellet) for 7 days. Tolerance to sufentanil was induced by subcutaneous implantation of osmotic minipumps for 7 days, which deliver at a rate of 2 micrograms/microliters/hr. Control groups received placebo pellets or minipumps of vehicle. Tolerance to morphine and DAMGO was observed after chronic treatment with morphine or sufentanil and was revealed as a rightward shift of the concentration-response curve. In addition, a decrease in maximal response was observed. Preparations from morphine-pelleted guinea pigs were also tolerant to the kappa-selective agonist trans-(+-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidynyl)- cyclohexyl]benzeneacetamide (U-50,488H); that is, there was cross-tolerance to the kappa agonist. The development of tolerance to U-50,488H was characterized by a parallel rightward shift of the concentration-response curve, but the maximal response was unchanged. Sufentanil-tolerant tissues were also tolerant to the inhibitory effects of U-50,488H (cross-tolerance). These data indicate that alterations occur during chronic mu opioid administration that are not receptor specific and suggest that tolerance would be associated with a functional change in the myenteric neurons that is unrelated to individual receptor system.
本研究旨在阐明豚鼠回肠肌间神经丛-纵行肌条中μ阿片受体的慢性激活是否会诱导对μ（特异性耐受）和κ激动剂（交叉耐受）产生耐受性。选用吗啡（μ激动剂的原型）、[D-Ala2，N-MePhe4，Gly-ol5]脑啡肽（DAMGO）和舒芬太尼（选择性μ激动剂）以及U-50,488H（选择性κ激动剂）。通过皮下植入吗啡丸（每丸75毫克）7天诱导对吗啡的耐受性。通过皮下植入渗透微型泵7天诱导对舒芬太尼的耐受性，微型泵以2微克/微升/小时的速率给药。对照组接受安慰剂丸或载体微型泵。在用吗啡或舒芬太尼进行慢性治疗后，观察到对吗啡和DAMGO的耐受性，表现为浓度-反应曲线向右移位。此外，观察到最大反应降低。来自植入吗啡丸的豚鼠的标本对κ选择性激动剂反式-（±）-3,4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]苯乙酰胺（U-50,488H）也具有耐受性；也就是说，对κ激动剂存在交叉耐受性。对U-50,488H耐受性的发展表现为浓度-反应曲线平行向右移位，但最大反应未改变。对舒芬太尼耐受的组织对U-50,488H的抑制作用也具有耐受性（交叉耐受）。这些数据表明，在慢性给予μ阿片类药物期间会发生非受体特异性的改变，并表明耐受性可能与肌间神经元的功能变化有关，而这种变化与单个受体系统无关。
