Locke K W, Holtzman S G
J Pharmacol Exp Ther. 1986 Sep;238(3):990-6.
The morphine-like discriminative stimulus effects of opioid peptides with selectivity for the mu- or delta-opioid receptors were examined in rats trained to discriminate 3.0 mg/kg of morphine (s.c.) from saline in a two-choice discrete-trial avoidance paradigm. The mu-selective peptides D-Ala2-NMePhe4-Gly5(ol)enkephalin, FK 33,824 and morphiceptin, the delta-selective peptides D-Ala2-D-Leu5enkephalin and metkephamid and beta-endorphin (mu- and delta-selective) produced morphine-like stimulus effects after administration into the lateral ventricle. Generalization with the morphine cue was dose-dependent and occurred over a wide range of doses (0.01-30 micrograms), depending upon peptide. On a molar basis, the order of relative potency of the peptides as morphine-like discriminative stimuli was: D-Ala2-NMePhe4-Gly5(ol)enkephalin = FK 33,824 greater than beta-endorphin greater than D-Ala2-D-Leu5enkephalin = metkephamid greater than morphiceptin. The discriminative effects of D-Ala2-NMePhe4-Gly5(ol)enkephalin, D-Ala2-D-Leu5enkephalin and beta-endorphin were antagonized by low doses of s.c. naltrexone (0.01-1.0 mg/kg). Furthermore, the stimulus effects of s.c. morphine were antagonized by 24-hr pretreatment of rats with the irreversible mu-antagonist beta-funaltrexamine (5.0 micrograms i.c.v.). Based upon the order of relative potency of the peptides and the relative potency for antagonism of their discriminative effects by naltrexone and beta-funaltrexamine, mu-opioid receptors in the brain appear to be an important element in the genesis of morphine-like discriminative effects by opioid peptides.
在一个两选择离散试验回避范式中,对训练成能区分3.0毫克/千克吗啡(皮下注射)和生理盐水的大鼠,研究了对μ或δ阿片受体有选择性的阿片肽的吗啡样辨别刺激效应。μ选择性肽D - Ala2 - NMePhe4 - Gly5(ol)脑啡肽、FK 33,824和吗啡肽,δ选择性肽D - Ala2 - D - Leu5脑啡肽和甲硫啡肽以及β - 内啡肽(μ和δ选择性)经侧脑室给药后产生吗啡样刺激效应。与吗啡线索的泛化是剂量依赖性的,且发生在很宽的剂量范围(0.01 - 30微克)内,具体取决于肽。以摩尔为基础,肽作为吗啡样辨别刺激的相对效价顺序为:D - Ala2 - NMePhe4 - Gly5(ol)脑啡肽 = FK 33,824 > β - 内啡肽 > D - Ala2 - D - Leu5脑啡肽 = 甲硫啡肽 > 吗啡肽。低剂量皮下注射纳曲酮(0.01 - 1.0毫克/千克)可拮抗D - Ala2 - NMePhe4 - Gly5(ol)脑啡肽、D - Ala2 - D - Leu5脑啡肽和β - 内啡肽的辨别效应。此外,用不可逆的μ拮抗剂β - 氟纳曲胺(5.0微克,脑室内注射)对大鼠进行24小时预处理可拮抗皮下注射吗啡的刺激效应。根据肽的相对效价顺序以及纳曲酮和β - 氟纳曲胺对其辨别效应拮抗的相对效价,脑内的μ阿片受体似乎是阿片肽产生吗啡样辨别效应过程中的一个重要因素。