Nation J R, Miller D K, Bratton G R
Department of Psychology, Texas A&M University, College Station 77843, USA.
Neurotoxicology. 2000 Aug;21(4):553-67.
This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.
本研究探讨了镉（所有烟草制品中高浓度存在的一种有毒物质）可能改变吗啡刺激特性的可能性。成年雄性大鼠被给予常规实验室饲料（对照组）或添加了100 ppm氯化镉的饲料（镉组）。在最初30天的暴露期后，对对照组和镉暴露组动物进行训练，使其在一项双选药物辨别任务中区分腹腔注射3.00 mg/kg硫酸吗啡和溶剂（蒸馏水）。随后，测定对照组和镉暴露组动物的吗啡剂量 - 效应泛化函数（0.75 - 6.00 mg/kg）。用递增剂量的高效μ激动剂芬太尼（0.0016 - 0.04 mg/kg）、中效μ激动剂（-）-美他佐辛（0.60 - 5.00 mg/kg）和κ激动剂（±）-布瑞马佐辛（0.03 - 0.12 mg/kg）进行了额外的替代试验。此外，用递增剂量的选择性μ拮抗剂纳洛酮（0.0008 - 0.50 mg/kg）对抗训练剂量的吗啡（3.00 mg/kg）和0.02 mg/kg芬太尼。最后，停止训练，在重新测定吗啡剂量效应函数之前，对照组和镉暴露组动物在饲养笼中每12小时注射8.00 mg/kg吗啡，持续2周。在停药1周的恢复期后，最后一次测定吗啡剂量效应函数。研究结果表明，镉暴露在不影响药物改变反应率特性的情况下，减缓了吗啡辨别的初始习得，降低了选择性剂量纳洛酮对抗吗啡和芬太尼刺激效应的效力，并阻断了对吗啡耐受性的形成。吗啡、芬太尼和（-）-美他佐辛在两组中的泛化（替代）情况相同，而（±）-布瑞马佐辛在两组中均不能替代吗啡刺激。这些发现为有关金属中毒与药物选择/滥用之间相互作用的文献增添了内容。
