Dopamine Dependence of Offset Analgesia

项目摘要 慢性疼痛是普遍存在的，昂贵的，和负担。患有慢性疼痛的人每天都会遭受痛苦-疼痛损害 他们的工作能力，移动，和生活自由。在社会层面上，慢性疼痛既给医疗保健系统带来压力， 和经济。尽管它的影响，没有治愈慢性疼痛。无法正确治疗慢性疼痛 导致了目前阿片类药物的流行。尽管我们现在开始了解 对于慢性疼痛，我们几乎没有评估和探索这些机制的方法。慢性疼痛生物标志物 与负责诱导和维持慢性疼痛的电路机械耦合将有助于 研究人员和临床医生治疗慢性疼痛。 偏置镇痛是一种心理物理现象，其特征是短暂的，不成比例的大 在伤害性刺激强度轻微降低后疼痛减轻。这种现象既是 从机理上和临床上都很有趣。从机制上讲，它将有害刺激与疼痛质量分离开来， 经常混淆的概念临床上，它在慢性疼痛患者中变钝，使其成为慢性疼痛的生物标志物。 痛苦然而，我们不知道如何抵消镇痛发生。通过阐明抵消镇痛的机制， 将对伤害性感受疼痛回路有更深入的了解。此外，它会改变抵消止痛 从慢性疼痛的心理物理学相关性到提供神经生理学见解的生物标志物。 该建议旨在评估抵消镇痛的多巴胺依赖性。虽然我们不知道抵消 镇痛的机制，一些证据表明它可能是多巴胺能。如果多巴胺假说 认为，那么负责慢性疼痛的核心机制也可能负责介导抵消 analgesia.目标1将尝试将抵消镇痛推广到其他伤害性刺激，因为以前的工作只有 测试了有害的热刺激。我们将比较热和冷之间的抵消镇痛反应和动力学 有害刺激建立冷抵消镇痛使我们能够通过确保 我们的结果并不特定于单一的模态。目的2：探讨丘脑底核的相关作用 抵消止痛如果中脑边缘系统负责抵消镇痛，其动力学应捕获 伤害性刺激（温度）和疼痛评级之间的时间分离。最后，在目标3中，我将获得 在Apkarian博士领导的一项临床试验中，使用哌醋甲酯扰乱多巴胺水平。一个 哌醋甲酯相对于安慰剂的抵消镇痛反应的增加表明多巴胺 依赖了解抵消镇痛的多巴胺依赖性对于了解其 潜在的机制及其作为慢性疼痛生物标志物的用途。

PROJECT SUMMARY Chronic pain is ubiquitous, costly, and burdensome. Individuals with chronic pain suffer daily—the pain impairs their ability to work, move, and live freely. On a societal level, chronic pain stresses both the healthcare system and the economy. Despite its impact, there is no cure for chronic pain. The inability to properly treat chronic pain has led to the current opioid epidemic. Although we are now beginning to understand the mechanisms underlying chronic pain, we have few ways of assessing and probing these mechanisms. A chronic pain biomarker mechanistically coupled to the circuitry responsible for inducing and maintaining chronic pain would help researchers study and clinicians treat chronic pain. Offset analgesia is a psychophysical phenomenon characterized by a transient, disproportionately large decrease in pain following a slight reduction in noxious stimulus intensity. This phenomenon is both mechanistically and clinically interesting. Mechanistically, it uncouples a noxious stimulus from pain qualia—two often-conflated constructs. Clinically, it is blunted in patients with chronic pain, making it a biomarker for chronic pain. Yet, we do not understand how offset analgesia occurs. By elucidating offset analgesia's mechanisms, we will gain a greater understanding of the nociceptive-pain circuitry. Moreover, it would transmute offset analgesia from a psychophysical correlate of chronic pain to a biomarker that provides neurophysiological insight. This proposal aims to assess the dopamine dependence of offset analgesia. Although we do not know offset analgesia's mechanisms, several lines of evidence suggest it may be dopaminergic. If the dopamine hypothesis holds, then the core mechanisms responsible for chronic pain may also be responsible for mediating offset analgesia. Aim 1 will attempt to generalize offset analgesia to other noxious stimuli since previous work has only tested noxious heat stimuli. We will compare the offset analgesic response and dynamics between hot and cold noxious stimuli. Establishing cold offset analgesia enables us to investigate its broader mechanisms by ensuring our results are not specific to a single modality. Aim 2 will investigate the correlative role of nucleus accumbens in offset analgesia. If the mesolimbic system is responsible for offset analgesia, its dynamics should capture the temporal dissociation between the noxious stimulus (temperature) and pain ratings. Finally, in Aim 3, I will gain experience in a clinical trial led by Dr. Apkarian that uses methylphenidate to perturb dopamine levels. An increase in the offset analgesic response with methylphenidate relative to placebo would indicate dopamine dependence. Understanding the dopamine dependence of offset analgesia is crucial to understanding its underlying mechanisms and its use as a chronic pain biomarker.