Curtright Andrew, Rosser Micaela, Goh Shamii, Keown Bailey, Wagner Erinn, Sharifi Jasmine, Raible David W, Dhaka Ajay
Department of Biological Structure, University of Washington, Seattle, Washington, 98195, United States of America.
Department of Biological Structure, University of Washington, Seattle, Washington, 98195, United States of America; Neurobiology and Behavior Graduate Program, University of Washington, Seattle, Washington, 98195, United States of America.
PLoS One. 2015 Jan 14;10(1):e0116766. doi: 10.1371/journal.pone.0116766. eCollection 2015.
Acute and chronic pain conditions are often debilitating, inflicting severe physiological, emotional and economic costs and affect a large percentage of the global population. However, the development of therapeutic analgesic agents based primarily on targeted drug development has been largely ineffective. An alternative approach to analgesic development would be to develop low cost, high throughput, untargeted animal based behavioral screens that model complex nociceptive behaviors in which to screen for analgesic compounds. Here we describe the development of a behavioral based assay in zebrafish larvae that is effective in identifying small molecule compounds with analgesic properties. In a place aversion assay, which likely utilizes supraspinal neuronal circuitry, individually arrayed zebrafish larvae show temperature-dependent aversion to increasing and decreasing temperatures deviating from rearing temperature. Modeling thermal hyperalgesia, the addition of the noxious inflammatory compound and TRPA1 agonist allyl isothiocyanate sensitized heat aversion and reversed cool aversion leading larvae to avoid rearing temperature in favor of otherwise acutely aversive cooler temperatures. We show that small molecules with known analgesic properties are able to inhibit acute and/or sensitized temperature aversion.
急慢性疼痛状况往往使人虚弱，造成严重的生理、情感和经济代价，影响着全球很大一部分人口。然而，主要基于靶向药物开发的治疗性镇痛药的研发在很大程度上是无效的。镇痛药开发的另一种方法是开发低成本、高通量、基于动物的非靶向行为筛选方法，以模拟复杂的伤害感受行为，从中筛选镇痛化合物。在此，我们描述了一种基于行为的斑马鱼幼体检测方法的开发，该方法能有效地识别具有镇痛特性的小分子化合物。在一种可能利用脊髓上神经回路的位置厌恶试验中，单独排列的斑马鱼幼体表现出对偏离饲养温度的温度升高和降低的温度依赖性厌恶。模拟热痛觉过敏，添加有害的炎症化合物和TRPA1激动剂异硫氰酸烯丙酯会使热厌恶敏感化，并逆转冷厌恶，导致幼体避开饲养温度，转而选择原本具有急性厌恶感的较低温度。我们表明，具有已知镇痛特性的小分子能够抑制急性和/或敏感化的温度厌恶。
