University of Zurich, Zurich Institute of Forensic Medicine, Department of Forensic Pharmacology and Toxicology, Zurich 8057, Switzerland; Eawag, Swiss Federal Institute of Aquatic Science and Technology, Department of Environmental Toxicology, Duebendorf 8600, Switzerland.
Eawag, Swiss Federal Institute of Aquatic Science and Technology, Department of Environmental Toxicology, Duebendorf 8600, Switzerland.
Toxicol Appl Pharmacol. 2021 May 15;419:115483. doi: 10.1016/j.taap.2021.115483. Epub 2021 Mar 13.
The number of new psychoactive substances (NPS) on the illicit drug market increases fast, posing a need to urgently understand their toxicity and behavioural effects. However, with currently available rodent models, NPS assessment is limited to a few substances per year. Therefore, zebrafish (Danio rerio) embryos and larvae have been suggested as an alternative model that would require less time and resources to perform an initial assessment and could help to prioritize substances for subsequent evaluation in rodents. To validate this model, more information on the concordance of zebrafish larvae and mammalian responses to specific classes of NPS is needed. Here, we studied toxicity and behavioural effects of opioids in zebrafish early life stages. Synthetic opioids are a class of NPS that are often used in pain medication but also frequently abused, having caused multiple intoxications and fatalities recently. Our data shows that fentanyl derivatives were the most toxic among the tested opioids, with toxicity in the zebrafish embryo toxicity test decreasing in the following order: butyrfentanyl>3-methylfentanyl>fentanyl>tramadol> O-desmethyltramadol>morphine. Similar to rodents, tramadol as well as fentanyl and its derivatives led to hypoactive behaviour in zebrafish larvae, with 3-methylfentanyl being the most potent. Physico-chemical properties-based predictions of chemicals' uptake into zebrafish embryos and larvae correlated well with the effects observed. Further, the biotransformation pattern of butyrfentanyl in zebrafish larvae was reminiscent of that in humans. Comparison of toxicity and behavioural responses to opioids in zebrafish and rodents supports zebrafish as a suitable alternative model for rapidly testing synthetic opioids.
新精神活性物质（NPS）在非法毒品市场上的数量迅速增加，因此迫切需要了解它们的毒性和行为效应。然而，目前可用的啮齿动物模型每年只能评估少数几种 NPS。因此，斑马鱼（Danio rerio）胚胎和幼虫已被提议作为替代模型，该模型需要更少的时间和资源来进行初步评估，并有助于优先选择随后在啮齿动物中进行评估的物质。为了验证这种模型，需要更多关于斑马鱼幼虫和哺乳动物对特定类别的 NPS 反应的一致性信息。在这里，我们研究了合成阿片类药物在斑马鱼早期生命阶段的毒性和行为效应。合成阿片类药物是一类 NPS，常用于止痛药，但也经常被滥用，最近导致了多次中毒和死亡。我们的数据表明，芬太尼衍生物是测试的阿片类药物中毒性最强的，在斑马鱼胚胎毒性试验中，毒性按以下顺序降低：丁酰芬太尼>3-甲基芬太尼>芬太尼>曲马多>O-去甲曲马多>吗啡。与啮齿动物相似，曲马多以及芬太尼及其衍生物导致斑马鱼幼虫表现出活动减少的行为，其中 3-甲基芬太尼的作用最强。基于理化性质的预测表明，化学物质在斑马鱼胚胎和幼虫中的摄取与观察到的效果相关。此外，丁酰芬太尼在斑马鱼幼虫中的生物转化模式与人类相似。斑马鱼和啮齿动物对阿片类药物的毒性和行为反应的比较支持斑马鱼作为快速测试合成阿片类药物的合适替代模型。
