Rowlett J K, Spealman R D
Harvard Medical School, New England Regional Primate Research Center, Southborough, MA 01772-9102, USA.
Psychopharmacology (Berl). 1998 Nov;140(2):217-24. doi: 10.1007/s002130050760.
Previous research in squirrel monkeys has shown enhancement of the discriminative stimulus effects of cocaine by mu-opioid agonists, but not by the delta agonist BW373U86. To examine further the role of mu and delta receptor stimulation in the ability of opioid drugs to modulate the discriminative stimulus effects of cocaine, the present study assessed the effects of cocaine alone and combined with SNC 80, a selective high-efficacy delta agonist, and fentanyl, a selective high-efficacy mu agonist. Five adult male squirrel monkeys were trained to discriminate i.m. injections of 0.3 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. Cumulative doses of cocaine (0.03-1.0 mg/kg) engendered dose-related increases in drug-lever responding to a maximum of 100%, with a decrease in response rate observed at 1.0 mg/kg. Cumulative doses of SNC 80 (0.03-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) resulted in a maximum of 22% and 48% drug-lever responding, respectively, accompanied by pronounced decreases in response rate. Administration of either SNC 80 (0.1-1.0 mg/kg) or fentanyl (0.001-0.01 mg/kg) prior to cumulative doses of cocaine produced dose-dependent leftward shifts in the cocaine dose-response function. When the selective delta antagonist naltrindole (1.0 mg/kg) was combined with SNC 80 (1.0 mg/kg) or fentanyl (0.01 mg/kg) prior to cumulative doses of cocaine, the leftward shift of the cocaine dose-response function produced by SNC 80 was blocked, whereas the leftward shift produced by fentanyl was not. By contrast, the mu antagonist naltrexone (0.3 mg/kg) blocked the cocaine-enhancing effects of fentanyl, but not of SNC 80. Combinations of SNC 80 (0.03-0.3 mg/kg) with fentanyl (0.001-0.003 mg/kg) resulted in leftward shifts in the cocaine dose-response function that were comparable in magnitude to the shifts in the cocaine dose-response function produced by either drug alone. These results suggest that opioid enhancement of the discriminative stimulus effects of cocaine is mediated independently by delta- and mu-receptor mechanisms.
先前对松鼠猴的研究表明，μ-阿片受体激动剂可增强可卡因的辨别刺激效应，但δ-阿片受体激动剂BW373U86却不能。为了进一步研究μ-和δ-受体刺激在阿片类药物调节可卡因辨别刺激效应能力中的作用，本研究评估了单独使用可卡因以及可卡因与选择性高效δ-激动剂SNC 80和选择性高效μ-激动剂芬太尼联合使用的效果。五只成年雄性松鼠猴接受训练，在固定比例为10的食物呈现时间表下，辨别肌肉注射0.3mg/kg可卡因与生理盐水。可卡因的累积剂量（0.03 - 1.0mg/kg）使药物杠杆反应呈剂量相关增加，最高可达100%，在1.0mg/kg时观察到反应率下降。SNC 80（0.03 - 1.0mg/kg）或芬太尼（0.001 - 0.01mg/kg）的累积剂量分别导致最高22%和48%的药物杠杆反应，同时伴有反应率明显下降。在可卡因累积剂量之前给予SNC 80（0.1 - 1.0mg/kg）或芬太尼（0.001 - 0.01mg/kg），会使可卡因剂量 - 反应函数产生剂量依赖性左移。当选择性δ-拮抗剂纳曲吲哚（1.0mg/kg）在可卡因累积剂量之前与SNC 80（1.0mg/kg）或芬太尼（0.01mg/kg）联合使用时，SNC 80产生的可卡因剂量 - 反应函数左移被阻断，而芬太尼产生的左移未被阻断。相比之下，μ-拮抗剂纳曲酮（0.3mg/kg）阻断了芬太尼增强可卡因的作用，但未阻断SNC 80的作用。SNC 80（0.03 - 0.3mg/kg）与芬太尼（0.001 - 0.003mg/kg）联合使用导致可卡因剂量 - 反应函数左移，其幅度与单独使用任何一种药物产生的可卡因剂量 - 反应函数左移相当。这些结果表明，阿片类药物对可卡因辨别刺激效应的增强作用是由δ-和μ-受体机制独立介导的。
