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Advancing understanding of anaesthesia and analgesia in the zebrafish

增进对斑马鱼麻醉和镇痛的了解

基本信息

批准号：
BB/V000411/1
负责人：
Charles Tyler
金额：
$ 73.4万
依托单位：
UNIVERSITY OF EXETER
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV000411%2F1
关键词：
Advancing understanding anaesthesia analgesia zebrafish

项目摘要

The zebrafish (Danio rerio) is used widely as a model for understanding biological processes in development and various human diseases. Features of embryonic and larval zebrafish (embryo-larvae, <10 days post fertilisation, or dpf) that make them highly attractive as a research model include their optical transparency for visualising biological processes and ease of genetic manipulation. Consequently, each year millions of embryo-larval zebrafish are used in laboratories across the globe. Many of these animals undergo anaesthesia, however, very little information is available to guide appropriate anaesthetic choice, and even less information is available on analgesics (pain relievers). Our project will address these knowledge gaps and has 3 main aims. Aim 1) Will establish the concentrations of anaesthetics needed to induce sedation and euthanasia, and the concentrations of analgesics needed to provide pain relief. For this we will use functional brain imaging (via fluorescent dyes that reveal the brain's neural activity) to test the responsiveness of animals to stimulation whilst under treatment. Electrophysiology (direct recording of the brain's electrical activity) will be used to establish concentrations of anaesthesia required for euthanasia. We will also gather data to understand if traditional indicators of sedation in fish are appropriate (e.g. loss of balance), and measure compound uptake to support interpretation of compound exposure effect concentrations. Aim 2) Will determine if any of the anaesthetics inhibit movement, if any of the anaesthetics and analgesics are aversive, and if any of the analgesics reduce the effects of noxious stimulation (e.g. heat, CO2). For this we will assess behaviour such as the effect of treatment on locomotion, and the avoidance of areas within a test arena where an anaesthetic or analgesic has been deposited. In addition, we will measure the ability of analgesics to decrease the behavioural impact of noxious stimuli as an indicator of their pain relieving properties. Aim 3) Will provide a better understanding of the mechanisms of action of the chosen anaesthetics and analgesics, and of sedation and pain perception in the embryo-larval zebrafish. For this we will undertake functional brain imaging in genetically-modified animals in which we are able to visualise activity in specific types of neuron in the brain. This will allow us to understand which brain regions and cell types respond to treatment with each agent, and which regions/cell types are involved in the sedative process. We will also apply this approach to animals subjected to noxious stimulation to better understand pain perception in fish. This project will allow scientists to select the most scientifically and ethically appropriate anaesthetic and analgesic for use in their work and will provide a better understanding of how these agents work, as well as advancing knowledge on the processes of sedation and pain perception in fish. Beneficiaries will include veterinary and aquarium fish industries as these data will help refine practices such as how best to monitor anaesthesia in fish, and inform on treatments most appropriate for animal transportation. Government bodies such as the UK Home Office, who oversee the scientific use of animals, will benefit through the provision of high quality reference data to use in decision making on animal experimentation practices, and charities ,such as those associated with neurological disorders (e.g. epilepsy, Alzheimer's, Parkinson's), will be provided with further validation data on an alternative (and more cost effective) model species. The public and society in general will benefit from an improvement in animal welfare standards, a greater understanding of sedation and pain perception, and an increase in our understanding of the biology of a species increasingly being used in experimental, including biomedical, research.

斑马鱼（Danio rerio）被广泛用作了解发育和各种人类疾病的生物过程的模型。胚胎和幼体斑马鱼（胚胎-幼体，受精后<10天，或dpf）的特征使它们作为研究模型非常有吸引力，包括它们的光学透明度，用于可视化生物过程和易于遗传操作。因此，每年有数百万的胚胎-幼体斑马鱼被用于地球仪的实验室。这些动物中有许多接受麻醉，然而，很少有信息可用于指导适当的麻醉剂选择，甚至更少的信息是关于镇痛药（止痛药）。我们的项目将解决这些知识差距，并有三个主要目标。目的1）将确定诱导镇静和安乐死所需的麻醉剂浓度，以及缓解疼痛所需的镇痛剂浓度。为此，我们将使用功能性脑成像（通过荧光染料显示大脑的神经活动）来测试动物在治疗期间对刺激的反应。电生理学（直接记录脑电活动）将用于确定安乐死所需的麻醉浓度。我们还将收集数据，以了解鱼类镇静的传统指标是否合适（例如失去平衡），并测量化合物的吸收，以支持化合物暴露效应浓度的解释。目的2）将确定是否有任何麻醉剂抑制运动，是否有任何麻醉剂和镇痛剂是厌恶性的，以及是否有任何镇痛剂减少有害刺激（例如，热、CO2）的影响。为此，我们将评估行为，如治疗对运动的影响，以及避免在试验竞技场内放置麻醉剂或止痛剂的区域。此外，我们将测量镇痛药减少有害刺激的行为影响的能力，作为其疼痛缓解特性的指标。目的3）将提供一个更好的了解所选择的麻醉剂和镇痛剂的作用机制，以及在胚胎-幼体斑马鱼的镇静和疼痛感知。为此，我们将在转基因动物中进行功能性脑成像，我们能够可视化大脑中特定类型神经元的活动。这将使我们能够了解哪些大脑区域和细胞类型对每种药物的治疗有反应，以及哪些区域/细胞类型参与了镇静过程。我们还将这种方法应用于受到伤害性刺激的动物，以更好地了解鱼类的疼痛感知。该项目将使科学家能够选择最科学和道德上合适的麻醉剂和止痛剂用于他们的工作，并将更好地了解这些药物如何工作，以及推进鱼类镇静和疼痛感知过程的知识。受益者将包括兽医和观赏鱼行业，因为这些数据将有助于改进实践，例如如何最好地监测鱼类的麻醉，并提供最适合动物运输的治疗方法。负责监督动物科学使用的英国内政部等政府机构将通过提供高质量的参考数据来用于动物实验实践决策而受益，而与神经系统疾病（例如癫痫、阿尔茨海默氏症、帕金森氏症）相关的慈善机构将获得有关替代（且更具成本效益）模型物种的进一步验证数据。公众和整个社会将受益于动物福利标准的提高，对镇静和疼痛感知的更好理解，以及我们对越来越多地用于实验（包括生物医学）研究的物种生物学的理解的增加。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Minimizing Experimental Testing on Fish for Legacy Pharmaceuticals.

最大程度地减少对遗产药物的鱼类的实验测试。

DOI：
10.1021/acs.est.2c07222
发表时间：
2023-01-31
期刊：
ENVIRONMENTAL SCIENCE & TECHNOLOGY
影响因子：
11.4
作者：
Coors, Anja;Brown, A. Ross;Maynard, Samuel K.;Perkins, Alison Nimrod;Owen, Stewart;Tyler, Charles R.
通讯作者：
Tyler, Charles R.

The diversity and evolution of electric organs in Neotropical knifefishes.

DOI：
10.1186/s13227-022-00194-5
发表时间：
2022-04-01
期刊：
EvoDevo
影响因子：
4.1
作者：
Bray IE;Alshami IJJ;Kudoh T
通讯作者：
Kudoh T

Molecular mechanisms of embryonic tail development in the self-fertilizing mangrove killifish Kryptolebias marmoratus.

DOI：
10.1242/dev.199675
发表时间：
2021-12-15
期刊：
Development (Cambridge, England)
影响因子：
0
作者：
Saud HA;O'Neill PA;Ono Y;Verbruggen B;Van Aerle R;Kim J;Lee JS;Ring BC;Kudoh T
通讯作者：
Kudoh T

Functional imaging in larval zebrafish for characterising the effects of proconvulsant compounds acting via a range of pharmacological mechanisms

斑马鱼幼虫的功能成像，用于表征促惊厥化合物通过一系列药理机制发挥作用的作用