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Abstract：
3,4-Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a selective μ-opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles in vivo remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for central nervous system (CNS) disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation evoked in fish by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples, supporting its permeability through the blood-brain barrier. Collectively, these findings emphasize complex dose- and treatment-dependent CNS effects of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing potential CNS effects evoked by novel synthetic opioid drugs.
摘要：
3,4-二氯-N-[2-（二甲基氨基）环己基]-N-甲基苯甲酰胺（U-47700）是一种选择性μ-阿片受体激动剂，最初是作为预期的镇痛药物合成的。比吗啡强几倍，U-47700具有很高的滥用潜力，可能引起临床神经毒性，欣快,呼吸抑制和偶尔死亡。U-47700也唤起了镇痛，人类和啮齿动物的镇静和兴奋状态。尽管U-47700的使用和滥用越来越多，但其在体内的精神药理学和毒理学特征仍然知之甚少。斑马鱼（Daniorerio）正在迅速成为一种流行的水生模式生物，用于中枢神经系统（CNS）疾病建模和药物发现。这里,我们检查了U-47700在成年斑马鱼中的急性（1、5、10、25和50mg/L持续20分钟）和慢性（0.1、0.5和1mg/L持续14天）作用。总的来说,我们发现在鱼类中引起明显的镇静作用，和过度运动，伴随着慢性的抗焦虑作用，药物治疗。用1和10mg/LU-47700的急性治疗也导致大脑样本中可检测到该药物的量，支持其通过血脑屏障的渗透性。总的来说，这些发现强调了U-47700急性和慢性给药后复杂的剂量和治疗依赖性中枢神经系统效应.我们的研究还支持斑马鱼对U-47700的高灵敏度，并建议这些水生模型作为有希望的体内筛选，用于探测新型合成阿片类药物引起的潜在中枢神经系统作用。
