Adams J U, Holtzman S G
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia.
J Pharmacol Exp Ther. 1990 May;253(2):483-9.
The pharmacologic specificity of the sensitization to naltrexone induced by acute opioid pretreatment was studied in rats trained to lever-press on a multiple-trial, fixed-interval 3-min schedule of food reinforcement. Cumulative doses of naltrexone were given until responding was suppressed; control naltrexone ED50 values for decreasing response rates ranged from 5.0 to 22 mg/kg. Agonists were administered 4 hr before naltrexone challenge. Pretreatment with morphine (10 mg/kg) initially produced a 4-fold shift to the left of the naltrexone dose-effect curve, but after repeated weekly testing with various agonists, produced a 1700-fold shift. Pretreatment with other millimicrons agonists (i.e., 0.3 mg/kg of levorphanol, 0.06 mg/kg of fentanyl and 3.0 mg/kg of methadone) produced similarly large (100- to 250-fold) increases in sensitivity to the rate-decreasing effects of naltrexone. On the other hand, pretreatment with agonists selective for kappa (1.0 mg/kg of ethylketocyclazocine and 3.0 mg/kg of U-50,488) or sigma (10 mg/kg of [+]-N-allylnormetazocine) receptors, produced smaller (10-fold) changes in sensitization to naltrexone. Neither dextrorphan (3.0 mg/kg) nor pentobarbital (18 mg/kg) pretreatment altered sensitivity to naltrexone. Thus, the sensitization to naltrexone induced by acute opioid pretreatment was a stereoselective, opioid-specific effect, and appeared to be mediated primarily by a mu-opioid mechanism. With repeated testing, the effect of acute morphine pretreatment was comparable to that reported after chronic administration, thus supporting the hypothesis that this phenomenon reflects receptor-mediated changes that underlie the state of opioid physical dependence.
在经过训练能按多次尝试、固定间隔3分钟食物强化程序压杆的大鼠中，研究了急性阿片类药物预处理诱导的对纳曲酮致敏的药理学特异性。给予累积剂量的纳曲酮直至反应被抑制；降低反应率的对照纳曲酮ED50值范围为5.0至22mg/kg。在纳曲酮激发前4小时给予激动剂。吗啡（10mg/kg）预处理最初使纳曲酮剂量-效应曲线向左移动4倍，但在每周用各种激动剂重复测试后，产生了1700倍的移动。用其他毫微克激动剂（即0.3mg/kg左啡诺、0.06mg/kg芬太尼和3.0mg/kg美沙酮）预处理对纳曲酮降低反应率的作用产生了类似的大幅（100至250倍）敏感性增加。另一方面，用对κ（1.0mg/kg乙基酮环唑辛和3.0mg/kg U-50,488）或σ（10mg/kg[+]-N-烯丙基去甲唑嗪）受体有选择性的激动剂预处理，对纳曲酮致敏的变化较小（10倍）。右啡烷（3.0mg/kg）或戊巴比妥（18mg/kg）预处理均未改变对纳曲酮的敏感性。因此，急性阿片类药物预处理诱导的对纳曲酮致敏是一种立体选择性、阿片类药物特异性效应，似乎主要由μ-阿片类机制介导。经过重复测试，急性吗啡预处理的效果与慢性给药后报道的效果相当，从而支持了这一假说，即这种现象反映了受体介导的变化，这些变化是阿片类药物身体依赖状态的基础。
