Kantak K M, Riberdy A, Spealman R D
Department of Psychology, Boston University, MA 02215, USA.
Psychopharmacology (Berl). 1999 Dec;147(3):257-65. doi: 10.1007/s002130051165.
The growing abuse of cocaine combined with morphine-like opiates ("speedballs") in human addicts has prompted efforts to characterize the roles of different opioid receptor subtypes in mediating their combined effects. Previous drug discrimination studies in rats have been inconsistent in showing significant interactions between cocaine and opioid agonists in subjects trained to discriminate a relatively high dose of cocaine from vehicle. It is known, however, that the training dose of cocaine can play a key role in drug-substitution and drug-interaction profiles and, therefore, training rats to discriminate a relatively low dose of cocaine may influence its interactions with opioid agonists.
The objectives of this study were to examine the degree to which a relatively high (10 mg/kg) versus a relatively low (3.0 mg/kg) cocaine training dose influenced the interactions between cocaine and either the mu opioid agonist morphine or the kappa opioid agonist U50,488.
Substitution tests with cumulative doses of cocaine, morphine and U50,488 were conducted, as were studies in which selected doses of morphine or U50,488 were administered prior to cumulative doses of cocaine.
In substitution tests, cocaine was 2.9 times more potent under the low- than the high-dose training condition. Morphine substituted fully for cocaine in the majority of subjects trained to discriminate the low, but not the high, dose of cocaine. U50,488 engendered mainly saline-lever responses under both training conditions. In pretreatment studies, morphine enhanced and U50,488 attenuated the discriminative stimulus effects of cocaine in low-dose, but not high-dose, trained rats. In low-dose trained rats, cocaine was five- to eightfold more potent after morphine and three- to fourfold less potent after U50,488 pretreatments.
The results demonstrate that cocaine-opioid interactions are dependent on the training dose of cocaine in rats and suggest an opposing influence of mu and kappa opioid receptors in modifying the discriminative stimulus effects of cocaine.
在人类成瘾者中，可卡因与吗啡样阿片类药物（“速球”）的滥用日益严重，这促使人们努力确定不同阿片受体亚型在介导其联合效应中的作用。先前在大鼠身上进行的药物辨别研究在显示可卡因与阿片类激动剂之间的显著相互作用方面并不一致，这些研究是在训练大鼠从溶剂中辨别相对高剂量可卡因的实验对象中进行的。然而，已知可卡因的训练剂量在药物替代和药物相互作用谱中可以发挥关键作用，因此，训练大鼠辨别相对低剂量的可卡因可能会影响其与阿片类激动剂的相互作用。
本研究的目的是检验相对高剂量（10毫克/千克）与相对低剂量（3.0毫克/千克）的可卡因训练剂量在多大程度上影响可卡因与μ阿片激动剂吗啡或κ阿片激动剂U50,488之间的相互作用。
进行了可卡因、吗啡和U50,488累积剂量的替代试验，以及在累积剂量的可卡因之前给予选定剂量的吗啡或U50,488的研究。
在替代试验中，在低剂量训练条件下，可卡因的效力比高剂量训练条件下高2.9倍。在大多数训练来辨别低剂量而非高剂量可卡因的实验对象中，吗啡完全替代了可卡因。在两种训练条件下，U50,488主要引发盐水杠杆反应。在预处理研究中，吗啡增强了低剂量训练大鼠而非高剂量训练大鼠中可卡因的辨别刺激效应，而U50,488则减弱了这种效应。在低剂量训练的大鼠中，吗啡预处理后可卡因的效力提高了五至八倍，而U50,488预处理后可卡因的效力降低了三至四倍。
结果表明，可卡因与阿片类药物的相互作用取决于大鼠体内可卡因的训练剂量，并提示μ和κ阿片受体在改变可卡因辨别刺激效应方面具有相反的影响。
