Identifying new targets in pain, utilizing the novel analgesic AS1

项目摘要 疼痛是患者寻求医疗保健的首要原因，超过20%的美国人口受到影响 慢性疼痛。现有的治疗方法具有有限的功效和狭窄的治疗期，同时也引起了对患者的不良反应。 有害的副作用因此，了解疼痛过程以开发新的 来解决这一紧迫的医疗危机。根据国际研究协会（International Association for the Study） 疼痛（IASP）疼痛是“与实际或潜在的疼痛相关的不愉快的感觉和情感体验”。 组织损伤”。由疼痛感知引起的情感痛苦的内在原因是消极的归因。 对伤害性刺激的效价。厌恶性动机回路的失调可能是大部分 与慢性疼痛状况相关的痛苦。快乐价是一种内在的 刺激的吸引力（积极）或厌恶（消极）。疼痛通常具有负效价， 通常是有利的，驱动自我保护行为。也许，人类有时可以将一个积极的 对伤害性刺激的效价;认为辛辣食物带来的快乐。这意味着分配的神经回路 对伤害性刺激的负效价是可延展的，并且疼痛和厌恶可以分离。关键是， 研究神经系统如何将效价分配给伤害性刺激的工具有限， 系统在这里，我们建议调查镇痛筛选1（AS 1）对伤害性加工的影响， 小分子，我们发现，扭转享乐动机（运动走向或远离）的 伤害性刺激包括热和有害化学物质异硫氰酸烯丙酯（AITC）在斑马鱼幼虫中， 使这些高度厌恶的刺激以剂量依赖的方式具有吸引力或有益。值得注意的是，AS 1 可以调节伤害性刺激的效价，将效价从厌恶转变为中性，再转变为吸引。AS1 没有预先确定的目标或功能。我们假设AS 1增强了 多巴胺奖赏系统通过D1受体激活，在存在多巴胺的情况下促进多巴胺的释放， 伤害性刺激这项提案的实验将利用斑马鱼的独特优势， 小鼠模型系统来测试这些假设，当完成时，我们将表征 AS 1对伤害感受的影响，并确定了AS 1在哪些神经回路上起作用以逆转伤害感受的效价。 从厌恶到吸引的刺激。在目的1中，我们提出确定AS 1对由以下引起的厌恶的影响： 伤害性和其他厌恶性刺激，以及这些刺激如何改变中枢神经系统中的神经元活动， 或在斑马鱼中不存在AS 1。在目标2中，我们将使用全面的遗传方法来评估 D1受体依赖性多巴胺能信号传导对存在或不存在伤害性刺激时由伤害性刺激引起的厌恶的影响 在斑马鱼中没有AS 1。在目标3中，我们将确定AS 1对伤害性感受，位置厌恶， 这些作用是否依赖于D1受体激活，以及AS 1在何处影响脑内神经元活动。 使用小鼠模型系统的CNS对伤害性刺激的响应。

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.