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An unbiased highthroughput behavior based screen for small molecule analgesics

基于无偏倚高通量行为的小分子镇痛药筛选

基本信息

批准号：
9241451
负责人：
AJAY K DHAKA
金额：
$ 19.31万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9241451
关键词：
Acute Acute Pain Adverse effects Affect Analgesics Animal Model Animals Behavior Behavioral Behavioral Assay Biological Assay Biological Models Complex Data Development Discrimination Disease Disease model Economic Burden Emotional Esthesia Failure Future Generations Human In Vitro Individual Inflammatory Injury Investments Larva Lead Modeling Motor Movement Neuraxis Nociception Pain Pathway interactions Peripheral Persistent pain Pharmaceutical Preparations Pharmacologic Substance Property Reflex action Rodent Rodent Model Safety Sensory Site Societies Stimulus Swimming Symptoms System Temperature Testing Thermal Hyperalgesias Vertebrates Zebrafish addiction avoidance behavior base chronic pain cost disabling symptom drug development drug discovery high throughput screening in vitro testing innovation model development neural circuit neuronal circuitry novel pain behavior pre-clinical preference public health relevance small molecule small molecule libraries success

项目摘要

DESCRIPTION (provided by applicant): Sensation of painful stimuli is critical for the survival. However, acute and chronic pain affects hundreds of millions of people as a result of injury, and is a debilitating symptom in many illnesses. Unfortunately, currently available drug based therapies have numerous deleterious side effects and/or potential for abuse and addiction, while also not being effective in the treatment of persistent pain. Despite massive investment, there has been limited success in the development of novel analgesic compounds. The dominant drug development model follows a predictable preclinical path in which a selected target is subjugated to high-throughput in vitro screens, the generation of lead compounds, and finally testing in disease model systems for safety and efficacy assessments. While this approach can be successful, it often leads to failure due to poor target selection, the inability to model complx pain behaviors using in vitro testing and/or ineffectiveness and unforeseen side effects in animal model testing. 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. In fact the most commonly used analgesics were identified due to their analgesic properties prior to target identification. Here w propose to use an alternative analgesic drug discovery approach by utilizing a novel zebrafish based behavioral assay to conduct a small molecule screen to identify novel analgesic compounds. The zebrafish provides an intriguing model system to study nociception. The neural circuits underling nociception in zebrafish larvae are highly analogous to those found in higher vertebrates such as rodents and humans. Furthermore we've shown that zebrafish larvae have a functionally diverse peripheral and central nervous system and respond robustly to noxious stimuli. Additionally zebrafish can be generated in large numbers at low costs and their small size allows for rapid upscaling using existing high throughput platforms, which is not possible with other vertebrate systems such as rodents. We will utilize a place aversion assay, which likely utilizes supraspinal nociceptive neuronal circuitry since the larvae must choose to avoid the noxious stimulus, to model sensitized thermal hyperalgesia, a symptom of many chronic pain diseases. In this assay individually arrayed zebrafish larvae show profound aversion to noxious temperature. Demonstrating that our place aversion reflects nociceptive behavior, small molecules with known analgesic properties potently reverse thermal aversion. In this exploratory study, utilizing the described assay, we propose to screen a 10,000 compound small molecule library for novel analgesic compounds. Identified molecules will be evaluated for their analgesic properties in future studies utilizing rodent model systems as well as for their site of action and could lead to the generation of novel analgesics. Findings from this proposal could provide a way forward for analgesic discovery that may offer a complementary parallel pathway to target-based drug development.