Morgan D, Picker M J
Department of Psychology, University of North Carolina at Chapel Hill, 27599-3270, USA.
Psychopharmacology (Berl). 1998 Nov;140(1):20-8. doi: 10.1007/s002130050734.
The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.
本研究的目的是使用不可逆的μ阿片受体拮抗剂β-芬太尼酰基去甲丙咪嗪（βFNA）来确定各种阿片类药物的相对内在效能。为此，在一个双按键、食物强化的药物辨别程序中，训练鸽子区分3.0（n = 6）或1.8（n = 1）mg/kg的吗啡与蒸馏水。μ阿片类药物芬太尼、左旋美沙酮、丁丙诺啡、布托啡诺、纳洛芬、纳布啡和左洛啡烷，以及δ阿片类药物BW373U86，完全替代了吗啡刺激。10 mg/kg剂量的βFNA可拮抗吗啡的刺激作用（即ED50值显著增加），但5 mg/kg剂量则不能。在2小时预处理后观察到βFNA的拮抗作用，但在26、50、74、98或146小时预处理后未观察到。芬太尼、左旋美沙酮和丁丙诺啡产生的刺激作用分别不受高达20、10和10 mg/kg剂量βFNA的拮抗。拮抗布托啡诺刺激作用所需的βFNA最低剂量为10 mg/kg，而纳洛芬、纳布啡和左洛啡烷的作用则可被低至5 mg/kg剂量的βFNA拮抗。δ型BW373U86替代了吗啡刺激，且这种作用不受10 mg/kgβFNA的拮抗。纳洛酮（1.0 mg/kg）对芬太尼（6.70）和吗啡（6.52）刺激作用的pKB值明显高于BW373U86（4.60），进一步表明BW373U86产生的吗啡样刺激作用不是由μ阿片受体的活性介导的。这些发现表明，在鸽子药物辨别程序中，不可逆拮抗策略可有效地用于区分在μ阿片受体上具有不同程度内在效能的阿片类药物。特别是，这些药物在μ阿片受体上按相对内在效能的排序为：左旋美沙酮 = 芬太尼 ≥ 丁丙诺啡 ≥ 吗啡 ≥ 布托啡诺 > 纳洛芬 = 纳布啡 = 左洛啡烷。此外，βFNA在鸽子中的短效作用表明μ阿片受体功能的恢复在不同物种间存在差异。
