Dopamine Dependence of Offset Analgesia

抵消镇痛的多巴胺依赖性

• 批准号: 10390003
• 负责人: Andrew Vigotsky
• 金额: $ 4.3万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390003
• 关键词: Absence of pain sensation; American; Analgesics; Biological Markers; Brain; Clinical; Clinical Trials; Coupled; Cross-Over Trials; Dangerousness; Dependence; Development; Diagnosis; Dissociation; Dopamine; Dopamine Receptor; Dopamine Uptake Inhibitors; Double-Blind Method; Economic Burden; Ensure; Exercise; Exhibits; Functional Magnetic Resonance Imaging; Future; Hand; Healthcare Systems; Image; Impairment; Individual; Intervention; Knowledge; Link; Maintenance; Mediating; Methods; Modality; Modeling; Neural Pathways; Nociception; Nucleus Accumbens; Opiate Addiction; Pain; Pain intensity; Participant; Patients; Perception; Pharmacology; Placebo Control; Placebos; Population; Prognosis; Psychophysics; Randomized; Research Personnel; Rewards; Ritalin; Role; Scanning; Science; Series; Specificity; Statistical Models; Stimulus; Stress; System; Temperature; Testing; Time; Training; Work; base; chronic pain; chronic pain management; chronic pain patient; clinically relevant; cost; daily pain; experience; experimental study; heat stimulus; hedonic; insight; mesolimbic system; multimodal neuroimaging; neurophysiology; novel; opioid epidemic; pain patient; patient population; response; social

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.

项目概要 慢性疼痛无处不在，费用高昂且负担重，患有慢性疼痛的人每天都会遭受痛苦——疼痛会损害患者的健康。 在社会层面上，慢性疼痛给医疗保健系统带来压力。 尽管有其影响，但慢性疼痛无法治愈。 导致了当前阿片类药物的流行，尽管我们现在开始了解其背后的机制。 慢性疼痛，我们几乎没有方法来评估和探索这些慢性疼痛生物标志物。 机械耦合到负责诱发和维持慢性疼痛的电路将有助于 研究人员研究和治疗慢性疼痛。 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 有害刺激强度轻微降低后疼痛减轻，这是两种现象。 从机制上和临床上来说，它把有害刺激与疼痛感受性分开——两种。 在临床上，它在慢性疼痛患者中被削弱，使其成为慢性疼痛的生物标志物。 然而，我们不了解偏置镇痛是如何发生的。通过阐明偏置镇痛的机制，我们。 将对伤害性疼痛回路有更深入的了解，此外，它将改变抵消镇痛作用。 从慢性疼痛的心理物理相关性到提供神经生理学见解的生物标志物。 该提案旨在评估抵消镇痛的多巴胺依赖性，尽管我们不知道抵消镇痛。 关于镇痛的机制，多项证据表明，如果多巴胺假说，它可能是多巴胺能的。 成立，那么造成慢性疼痛的核心机制也可能负责调节抵消 目标 1 将尝试将抵消镇痛推广到其他有害刺激，因为之前的工作仅 我们将比较热和冷之间的抵消镇痛反应和动力学。 建立冷补偿镇痛使我们能够通过确保其更广泛的机制。 我们的结果并不特定于单一模式。目标 2 将研究伏隔核的相关作用。 如果中脑边缘系统负责偏置镇痛，那么它的动态应该捕捉到 最后，在目标 3 中，我将获得有害刺激（温度）和疼痛等级之间的时间分离。 Apkarian 博士领导的一项使用哌醋甲酯扰乱多巴胺水平的临床试验的经验。 相对于安慰剂，哌醋甲酯抵消镇痛反应的增加表明多巴胺 了解抵消镇痛的多巴胺依赖性对于理解其依赖性至关重要。 潜在机制及其作为慢性疼痛生物标志物的用途。