Suzuki T, Mori T, Tsuji M, Maeda J, Kishimoto Y, Misawa M, Nagase H
Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Eur J Pharmacol. 1997 Apr 11;324(1):21-9. doi: 10.1016/s0014-2999(97)00062-9.
The effects of selective mu-, delta- and kappa-opioid receptor agonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Cocaine produced a dose-related increase in cocaine-appropriate responses in all of the rats. In generalization tests, neither morphine (mu-opioid receptor agonist) nor N-methyl-N-7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-11-4-benzofu ranacetamide (U50,488H: kappa-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. On the other hand, the newly synthesized non-peptide selective delta-opioid receptor agonist 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydro-quinolino(2,3,3,-g)isoquinoline (TAN-67) partially generalized (56.7% cocaine-appropriate responses) to the discriminative stimulus properties of cocaine. Intracerebroventricular (i.c.v.) administration of [D-Ala2]deltorphin II (peptide delta 2-opioid receptor agonist) completely generalized, while neither [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO: mu-opioid receptor agonist) nor [D-Pen2,D-Pen5]enkephalin (DPDPE; delta 1-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. These results suggest that the discriminative stimulus properties of cocaine may be partially mediated by delta-opioid (especially delta 2-opioid) receptors. In combination tests, pretreatment with morphine (3.0 mg/kg) and TAN-67 (3.0 and 10 mg/kg) significantly potentiated the discriminative stimulus properties cocaine. In contrast, pretreatment with U50,488H (2.0 and 4.0 mg/kg) scarcely shifted the discriminative stimulus properties of cocaine. Furthermore, the potentiating effect of 3.0 mg/kg morphine on the discriminative stimulus properties of cocaine was attenuated by 2.0 mg/kg U50,488H. In contrast, the potentiating effect of 10 mg/kg TAN-67 on the discriminative stimulus properties of cocaine was not reversed by either 2.0 or 4.0 mg/kg U50,488H. These results suggest that mu-, delta- and kappa-opioid receptor agonists modulate the discriminative stimulus properties of cocaine through different mechanisms, perhaps through different effects on the dopaminergic system.
在经过训练以区分可卡因（10毫克/千克）和生理盐水的大鼠中，研究了选择性μ-、δ-和κ-阿片受体激动剂对可卡因辨别刺激特性的影响。可卡因使所有大鼠中与可卡因相关的反应呈剂量依赖性增加。在泛化试验中，吗啡（μ-阿片受体激动剂）和N-甲基-N-7-(1-吡咯烷基)-1-氧杂螺[4,5]癸-8,11-4-苯并呋喃乙酰胺（U50,488H：κ-阿片受体激动剂）均未泛化至可卡因的辨别刺激特性。另一方面，新合成的非肽选择性δ-阿片受体激动剂2-甲基-4aα-(3-羟基苯基)-1,2,3,4,4a,5,12,12aα-八氢喹啉并(2,3,3,-g)异喹啉（TAN-67）部分泛化（56.7%与可卡因相关的反应）至可卡因的辨别刺激特性。脑室内（i.c.v.）注射[D-Ala2]强啡肽II（肽δ2-阿片受体激动剂）完全泛化，而[D-Ala2,MePhe4,Gly-ol5]脑啡肽（DAMGO：μ-阿片受体激动剂）和[D-Pen2,D-Pen5]脑啡肽（DPDPE；δ1-阿片受体激动剂）均未泛化至可卡因的辨别刺激特性。这些结果表明，可卡因的辨别刺激特性可能部分由δ-阿片（尤其是δ2-阿片）受体介导。在联合试验中，用吗啡（3.0毫克/千克）和TAN-67（3.0和10毫克/千克）预处理显著增强了可卡因的辨别刺激特性。相比之下，用U50,488H（2.0和4.0毫克/千克）预处理几乎未改变可卡因的辨别刺激特性。此外，3.0毫克/千克吗啡对可卡因辨别刺激特性的增强作用被2.0毫克/千克U50,488H减弱。相反，10毫克/千克TAN-67对可卡因辨别刺激特性的增强作用未被2.0或4.0毫克/千克U50,488H逆转。这些结果表明，μ-、δ-和κ-阿片受体激动剂通过不同机制调节可卡因的辨别刺激特性，可能是通过对多巴胺能系统的不同作用。
