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.

项目总结 慢性疼痛无处不在，代价高昂，负担沉重。患有慢性疼痛的人每天都会遭受痛苦-这种疼痛会损害 他们自由工作、行动和生活的能力。在社会层面上，慢性疼痛给医疗保健系统带来压力 和经济。尽管有影响，但慢性疼痛无法治愈。无法正确治疗慢性疼痛 导致了目前的阿片类药物流行。尽管我们现在开始了解潜在的机制 对于慢性疼痛，我们几乎没有方法来评估和探索这些机制。一种慢性疼痛生物标志物 机械地耦合到负责诱导和维持慢性疼痛的回路将会有所帮助 研究人员研究和临床医生治疗慢性疼痛。 抵消止痛是一种心理物理现象，其特征是一过性的，不成比例的大 伤害性刺激强度稍有降低后疼痛减轻。这种现象既是 机械上和临床上都很有趣。从机械上讲，它将有害的刺激从疼痛中分离出来--2 经常合并在一起的构造。在临床上，它在慢性疼痛患者中被钝化，使其成为慢性疼痛的生物标志物。 疼痛。然而，我们不知道抵消止痛是如何发生的。通过阐明抵消止痛的机制，我们 将对伤害性痛觉回路有更深入的了解。此外，它还会改变抵销止痛。 从慢性疼痛的心理物理关联到提供神经生理洞察力的生物标记物。 这项建议旨在评估多巴胺对抵消镇痛的依赖性。虽然我们不知道偏移量 关于止痛的机制，有几条证据表明它可能是多巴胺能的。如果多巴胺假说 坚持认为，那么负责慢性疼痛的核心机制可能也负责调节抵消 止痛药。目标1将尝试将抵消止痛推广到其他有害刺激，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止痛反应和动力学 有害的刺激。建立冷补偿镇痛使我们能够通过确保 我们的结果并不特定于单一的医疗模式。目的2研究伏隔核的相关作用 在抵消止痛方面。如果中脑边缘系统负责抵消止痛，它的动力学应该捕捉到 伤害性刺激(温度)和疼痛等级之间的时间分离。最后，在《目标3》中，我将收获 阿普卡里安博士领导的一项临床试验的经验，该试验使用哌醋甲酯来扰乱多巴胺水平。一个 与安慰剂相比，与安慰剂相比，哌醋甲酯的抵消止痛反应增加可能表明多巴胺 依赖。了解多巴胺对抵消镇痛的依赖对于理解其 潜在机制及其作为慢性疼痛生物标记物的应用。