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.

项目摘要 慢性疼痛无处不在，昂贵且朴素。患有慢性疼痛的人每天遭受疼痛 他们的工作，移动和自由生活的能力。在社会层面上，慢性疼痛强调医疗保健系统 和经济。尽管有影响，但仍无法治愈慢性疼痛。无法正确治疗慢性疼痛 导致当前的阿片类药物流行。尽管我们现在开始理解基本机制 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 机械上耦合到负责诱发和维持慢性疼痛的电路将有助于 研究人员研究和临床医生治疗慢性疼痛。 抵消镇痛是一种心理物理现象，其特征是短暂的，不成比例的 有害刺激强度略微降低后，疼痛减轻。这个现象都是 机械和临床上有趣。从机械上讲，它从疼痛质量中解脱出一种有害的刺激 - 两个 经常汇合的结构。临床上，它在慢性疼痛的患者中钝化，使其成为慢性的生物标志物 疼痛。但是，我们不了解止痛镇的发生方式。通过阐明抵消镇痛的机制，我们 将对伤害感受性疼痛电路有了更大的了解。此外，它将传递抵消镇痛 从慢性疼痛的心理物理相关性到提供神经生理见解的生物标志物。 该提案旨在评估止痛镇痛的多巴胺依赖性。虽然我们不知道偏移 镇痛的机制，几条证据表明它可能是多巴胺能。如果多巴胺假说 持有，那么负责慢性疼痛的核心机制也可能负责介导偏移 镇痛。 AIM 1将尝试将镇痛元素概括为其他有害刺激，因为以前的工作仅具有 测试了有害热刺激。我们将比较偏移型镇痛反应和热和冷的动态 有害刺激。建立冷抵消镇痛使我们能够通过确保确保调查其更广泛的机制 我们的结果并非特定于单一模态。 AIM 2将研究伏隔核的相关作用 在止痛药中。如果中唇系统负责抵消镇痛，则其动态应捕获 有害刺激（温度）和疼痛等级之间的暂时解离。最后，在AIM 3中，我会收获 Apkarian博士领导的一项临床试验的经验，该试验使用哌醋甲酯扰动多巴胺水平。一个 相对于安慰剂而言，用哌醋甲酯的止痛镇痛反应增加将表明多巴胺 依赖。了解止痛镇痛的多巴胺依赖性对于理解其 基本机制及其用作慢性疼痛生物标志物。