Johnson-Davis Kamisha L, Hanson Glen R, Keefe Kristen A
Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Rm. 201, Salt Lake City, UT 84112, USA.
Neurotox Res. 2003;5(4):273-81. doi: 10.1007/BF03033385.
High-dose methamphetamine treatment induces long-term deficits in central monoamine systems. However, the mechanisms underlying these effects are unknown. Previous work has shown that the Kappa-opioid receptor agonist U-69593 [(+)-(5alpha,7alpha,8b)-(+)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl] benzeneacetamide] attenuates the neurotoxic effects of methamphetamine on extracellular dopamine levels in mice, suggesting that endogenous Kappa-opioid receptor ligands, such as dynorphin, may protect against methamphetamine-induced toxicity and play a role in mediating the long-term consequences of methamphetamine. To further examine the role that dynorphin systems play in methamphetamine-induced neurotoxicity, we administered to male rats a total of four injections of methamphetamine (7.5 mg/kg, s.c.), with a 2-h interval between each dose. Rats were pretreated with either the Kappa-agonist U-69593 (0.32 mg/kg, s.c.) or vehicle, 15 min prior to the first and third methamphetamine injection. Furthermore, cages containing the U-69593 + methamphetamine-treated rats were placed on heating pads for 30 min after the first U-69593 injection to prevent the drug from blocking methamphetamine-induced hyperthermia. Rats were sacrificed 7 days after treatment. Striatal dopamine and serotonin contents were decreased approximately 75% and 55%, respectively, in the methamphetamine-treated rats and approximately 88% and 65%, respectively, in rats receiving the U-69593 + methamphetamine combination. There was a approximately 20% mortality rate in the rats treated with methamphetamine compared to approximately 75% mortality rate in rats treated with both U-69593 and methamphetamine. A similar rate of mortality was observed when combining a different Kappa-agonist, U-50488 [trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamine], with methamphetamine. These data suggest that Kappa-agonists do not protect against methamphetamine-induced toxicity to monoamines in rats, and may potentiate mortality when co-administered with methamphetamine.
高剂量甲基苯丙胺治疗会导致中枢单胺系统出现长期缺陷。然而，这些效应背后的机制尚不清楚。先前的研究表明，κ-阿片受体激动剂U-69593 [（+）-（5α，7α，8b）-（+）-N-甲基-N [7-（1-吡咯烷基）-1-氧杂螺[4.5]癸-8-基]苯乙酰胺]可减轻甲基苯丙胺对小鼠细胞外多巴胺水平的神经毒性作用，这表明内源性κ-阿片受体配体，如强啡肽，可能对甲基苯丙胺诱导的毒性具有保护作用，并在介导甲基苯丙胺的长期后果中发挥作用。为了进一步研究强啡肽系统在甲基苯丙胺诱导的神经毒性中所起的作用，我们给雄性大鼠总共注射了四次甲基苯丙胺（7.5毫克/千克，皮下注射），每次剂量之间间隔2小时。在第一次和第三次甲基苯丙胺注射前15分钟，大鼠分别用κ-激动剂U-69593（0.32毫克/千克，皮下注射）或赋形剂进行预处理。此外，在第一次注射U-69593后，将装有U-69593 + 甲基苯丙胺处理大鼠的笼子放在加热垫上30分钟，以防止药物阻断甲基苯丙胺诱导的体温过高。治疗7天后处死大鼠。在甲基苯丙胺处理的大鼠中，纹状体多巴胺和血清素含量分别降低了约75%和55%，在接受U-69593 + 甲基苯丙胺联合处理的大鼠中分别降低了约88%和65%。与同时接受U-69593和甲基苯丙胺处理的大鼠约75%的死亡率相比，接受甲基苯丙胺处理的大鼠死亡率约为20%。当将另一种κ-激动剂U-50488 [反式-（-）-3,4-二氯-N-甲基-N-[2-（1-吡咯烷基）环己基]苯乙酰胺]与甲基苯丙胺联合使用时，观察到了类似的死亡率。这些数据表明，κ-激动剂不能保护大鼠免受甲基苯丙胺诱导的单胺毒性，并且与甲基苯丙胺共同给药时可能会增加死亡率。
