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Identifying new targets in pain, utilizing the novel analgesic AS1

利用新型镇痛药 AS1 确定疼痛的新靶点

基本信息

批准号：
10307581
负责人：
AJAY K DHAKA
金额：
$ 37.4万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10307581
关键词：
Ablation Address Affect Analgesics Automobile Driving Aversive Stimulus Behavioral Biological Models Chemicals Complex Data Development Diffuse Disease Dopamine Dopamine D1 Receptor Dose Emotional Esthesia Food Formalin Gene Deletion Generations Healthcare Human Inflammatory Injections International Mammals Maps Measurement Mediating Mission Mood Disorders Motivation Movement Mus Negative Valence Nervous system structure Neurons Neurotransmitters Nociception Nociceptive Stimulus Nucleus Accumbens Pain Pathway interactions Patients Phase Population Positive Valence Receptor Activation Research Rewards Role Sensory Signal Transduction Site Stimulus System Testing Therapeutic Time Tissues United States National Institutes of Health Vertebrates Zebrafish allyl isothiocyanate antagonist base chronic pain chronic pain management chronic painful condition emotional experience experimental study genetic approach hedonic mouse model neural circuit neuronal circuitry novel novel therapeutics optogenetics pain perception pain processing pleasure preference protective behavior relating to nervous system response side effect small molecule small molecule libraries tool

项目摘要

Project Summary Pain is the number one reason patients seek health care and greater than 20% of the US population is affected by chronic pain. Existing therapeutics have limited efficacy and a narrow therapeutic period, while also evoking deleterious side effects. It is therefore vital to understand pain processing in order to develop novel therapeutics to address this pressing health care crisis. According to the International Association for the Study of Pain (IASP) pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage”. Intrinsic to the emotional suffering elicited by pain perception is the attribution of a negative valence to nociceptive stimuli. Dysregulation of aversive motivational circuits may underlie much of the suffering associated with chronic pain conditions. Hedonic valence is a measurement of the intrinsic attractiveness (positive) or averseness (negative) of a stimulus. Pain typically has a negative valence, which is normally advantageous, driving self-protective behavior. Perversely, humans can sometimes assign a positive valence to nociceptive stimuli; think pleasure from spicy foods. This implies that the neural circuits that assign negative valence to nociceptive stimuli are malleable and that pain and aversion can be decoupled. Critically, there have been limited tools to investigate how valence is assigned to nociceptive stimuli by the nervous system. Here, we propose to investigate the effects on nociceptive processing by Analgesic Screen 1 (AS1), a small molecule we discovered that reverses the hedonic motivation (movement toward or away from) of nociceptive stimuli including heat and the noxious chemical allyl isothiocyanate (AITC) in larval zebrafish, rendering these highly aversive stimuli attractive or rewarding in a dose dependent manner. Remarkably, AS1 can tune the valence of nociceptive stimuli, transforming the valence from aversive to neutral to attractive. AS1 has no previously identified target or function. We hypothesize that AS1 potentiates the activity of the dopamine reward system via D1 receptor activation by promoting release of dopamine in the presence of nociceptive stimuli. Experiments in this proposal will make use of the unique advantages of the zebrafish and mouse model systems to test these hypotheses and when completed, we will have characterized the effects of AS1 on nociception and identified upon which neural circuits AS1 acts to invert the valence of nociceptive stimuli from aversive to attractive. In Aim 1, we propose to determine the effects of AS1 on aversion evoked by nociceptive and other aversive stimuli and how these stimuli alter neuronal activity in the CNS in the presence or absence of AS1 in zebrafish. In Aim 2, we will use a comprehensive genetic approach to assess the role of D1 receptor dependent dopaminergic signaling on aversion elicited by nociceptive stimuli in the presence or absence of AS1 in zebrafish. In Aim 3, we will ascertain the effect of AS1 on nociception, place aversion, whether these effects are dependent on D1 receptor activation and where AS1 effects neuronal activity in the CNS in response to nociceptive stimuli using the mouse model system.

项目总结