Ural Federal University, Ekaterinburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Center, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Laboratory of Biological Psychiatry, Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia.
Ural Federal University, Ekaterinburg, Russia.
Brain Res Bull. 2021 Feb;167:48-55. doi: 10.1016/j.brainresbull.2020.11.017. Epub 2020 Nov 26.
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.
3,4-二氯-N-[2-(二甲氨基)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，最初被合成作为一种有前途的镇痛药物。U-47700 的效力比吗啡强几倍，具有高度的滥用潜力，并可能导致临床神经毒性、欣快、呼吸抑制和偶尔的死亡。U-47700 还能引起人类和啮齿动物的镇痛、镇静和欣快样状态。尽管 U-47700 的使用和滥用不断增加，但它在体内的精神药理学和毒理学特征仍知之甚少。斑马鱼（Danio rerio）正在迅速成为中枢神经系统（CNS）疾病建模和药物发现的流行水生模式生物。在这里，我们研究了 U-47700 在成年斑马鱼中的急性（1、5、10、25 和 50mg/L 处理 20 分钟）和慢性（0.1、0.5 和 1mg/L 处理 14 天）效应。总的来说，我们发现急性处理会引起鱼明显的镇静作用，慢性处理则会引起鱼过度运动和具有抗焦虑样作用。急性处理 1 和 10mg/L 的 U-47700 也会导致大脑样本中检测到这种药物的存在，支持它可以穿过血脑屏障。总的来说，这些发现强调了 U-47700 急性和慢性给药后对中枢神经系统的复杂剂量和处理依赖性影响。我们的研究还支持斑马鱼对 U-47700 的高敏感性，并表明这些水生模型是探测新型合成阿片类药物引起的潜在中枢神经系统效应的有前途的体内筛选模型。
