Etanercept: a Mechanistic Probe of Central Mu-Opioid Dysregulation in Pain States

依那西普：疼痛状态中枢 Mu-阿片类药物失调的机制探讨

• 批准号: 8280767
• 负责人: Alan Rodney Prossin
• 金额: $ 17.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280767
• 关键词: Acute Pain; Address; Amygdaloid structure; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Area; Award; Behavioral; Biological; Biological Assay; Brain; Brain region; Chronic inflammatory pain; Clinical; Comorbidity; Conflict (Psychology); Consultations; Data; Development; Down-Regulation; Emotional Stress; Engineering; Environment; Equilibrium; Etanercept; Etiology; FDA approved; Faculty; Family; Fibromyalgia; Functional disorder; Goals; Grant; Health; Human; Hypersensitivity; Hypothalamic structure; Immune; Immunology; Inflammatory; Institutes; Interleukin-1; Lead; MRI Scans; Measurement; Measures; Mediating; Mental Depression; Mentors; Mentorship; Michigan; Mission; Modeling; Molecular; Mood Disorders; Nature; Neurons; Neurotransmitters; Nociception; Opiates; Opioid; Opioid Receptor; Pain; Pain Research; Pattern; Peripheral; Persistent pain; Pharmaceutical Preparations; Physicians; Physics; Placebos; Play; Population; Positioning Attribute; Positron-Emission Tomography; Process; Psychiatrist; Psychiatry; Psychoneuroimmunology; Public Health; Radiology Specialty; Recovery; Regulation; Research; Research Personnel; Research Training; Rewards; Role; Sampling; Scientist; Signal Transduction; Statistical Methods; Stress; Symptoms; Syndrome; System; TNF gene; Techniques; Testing; Training; Training and Education; Translations; Tumor Necrosis Factor-alpha; United States National Institutes of Health; Universities; Ventral Striatum; anakinra; base; biological adaptation to stress; chronic pain; clinical efficacy; clinically relevant; computerized data processing; cytokine; depressive symptoms; effective therapy; emotion regulation; endogenous opioids; expectation; human TNF protein; in vivo; innate immune function; interest; lecturer; midbrain central gray substance; mind body interaction; mu opioid receptors; neuroimaging; neurotransmission; novel; patient oriented; response; restoration; skills; statistical center; stressor; tool; treatment strategy

DESCRIPTION (provided by applicant): The overarching goal of this K99/R00 proposal is to further the candidate's expertise in the immunological bases of persistent pain conditions and their co-morbidity with depressive symptoms. More specifically, the candidate seeks to develop expertise in the utilization of PET neuroimaging techniques as an investigational tool in understanding the role of immune factors in the pathophysiology of chronic pain states such as Fibromyalgia (FM). Such research is well positioned to discover the mechanisms underlying many "mind-body" interactions in chronic pain states like FM. Candidate: The candidate's education and training thus far have prepared him well for the proposed grant. A Clinical Lecturer of Psychiatry at the University of Michigan, the candidate is trained as an engineer, psychiatrist, and PET neuroimager with an evolving research interest in the role of inflammatory cytokines in depression and pain states. As such, he is well poised to advance patient-oriented psychoneuroimmunology research. However, to achieve full research independence and obtain a competitive tenure track faculty position, he has defined specific areas requiring further/supplemental training: 1) chronic pain research, 2) innate immune functioning (enhancing practical cytokine assay skills), 3) advanced statistical techniques, and 4) PET neuroimaging advanced analytic techniques. Environment: The candidate will benefit from established collaborative relationships between researchers in psychiatry and other departments at the University of Michigan (i.e., Radiology, Michigan Institute for Clinical and Health Research, Center for Statistical Consultation and Research). The candidate has access to PET and MRI scanning facilities, cytokine assay labs, and a wide range of clinical samples. Dr. Jon-Kar Zubieta, the candidate's primary mentor, has an established record as both mentor and productive neuroscientist with 15 years of expertise in PET neuroimaging of depression and pain. Two additional internal mentors, Drs. Daniel Clauw (pain) and Alisa Koch (immunology), and one external mentor, Dr. Steven Zalcman (behavioral consequences of cytokine challenge), will round out the mentorship team. Consultants, one external (Dr. Andrew Miller) and two internal (Dr. Robert Koeppe and Dr. Edward Rothman), will provide expert consultation in using TNF-alpha antagonists (i.e. etanercept) as an inflammatory challenge, PET neuroimaging physics, and statistical methods, respectively. Research: Spanning the award duration, the proposed research plan focuses on determining the role of inflammatory cytokines in the pathophysiology of chronic pain states (i.e. FM). FM is a common, debilitating illness, and a significant public health concern. Etanercept, a cytokine (i.e. TNF-alpha) antagonist, is proposed as a mechanistic probe to differentiate causality from epi-phenomena in determining the role that cytokines play in the dysregulaton of central mu-opioid receptor mediated anti-nociceptive mechanisms in FM. Current understanding of the biological underpinnings of FM is marked by equivocal findings. Some data suggest the underlying dysregulation in FM is central, such as a down-regulation of mu-opioid receptor mediated neurotransmission, while other data suggest dysregulated peripheral nociceptive mechanisms involving pro-inflammatory cytokines. Preliminary data suggests that both peripheral and central mechanisms are involved, and further, interact with each other, potentially perpetuating the persistence of pain. Indeed, pro-inflammatory cytokines (i.e. TNF-alpha, IL-1beta) are implicated in hypernociceptive states (i.e. pain hypersensitivity in FM) in humans and animal models. Pro- inflammatory cytokine antagonists (i.e., etanercept), have been shown in animal models to reverse this hyper-nociceptive state. However, in-vivo human research is limited by the lack of available research paradigms to mechanistically unravel the underpinnings of FM. Preliminary data shows that pro-inflammatory cytokines are associated with activation, and potential dysregulation of central mu-opioid neurotransmitter function in pain states, depression, and in response to pain and emotional stress. These data specifically implicate the ventral striatum and amygdala, regions involved in encoding salient and stressful signals, rewarding and aversive. Further, these data implicate anti-inflammatory cytokines (i.e. IL-1ra,sTNF-alphaR1) as having opposing effects on mu-opioid receptor availability in vivo in these same regions. However, differentiating causality from epi-phenomena is a necessary step in translation to novel treatment strategies. Given its direct and indirect action on inflammatory cytokines central to rheumatological processes, and the data illustrating cytokine involvement in hypernociceptive states and central opioid functional measures, etanercept is ideally suited to this task. Specific AIMS: Aim 1: To determine the presence of moderate sustained pain stress induced changes in central MOR mediated neurotransmission (and peripheral inflammatory state) in chronic pain. Aim 2: To show that lower baseline MOR BPND (and higher pro-inflammatory cytokine concentrations) will predict response to etanercept pre-treatment, in FM. Summary: This K99/R00 proposal is well aligned with missions of the NIH (PA-10-006: Mechanisms, Models, Measurement, & Management in Pain Research). The project will provide a promising junior investigator with additional training requisite to his traversal to independence as a clinical translational psychoneuroimmunologist. Simultaneously, the project will address important, testable questions regarding the poorly understood mechanistic underpinnings of acute and chronic pain states such as FM. PUBLIC HEALTH RELEVANCE: The proposed K99/R00 project serves dual purposes: (1) to expand the research training of a promising physician-scientist to become an independent investigator in psychoneuroimmunology research of chronic pain states, and (2) to utilize etanercept, an anti-inflammatory medication, as an inflammatory probe, artificially altering the circulating inflammatory cytokine milieu, discerning causality from epi-phenomena in the relationship between cytokines and mu-opioid functioning in pain states. Accomplishment of these two objectives will address the recognized shortage of physician scientists that are pursuing translational psychoneuroimmunology research in chronic pain states, and will simultaneously answer clinically relevant questions about common, disabling illnesses that too often fail to respond to current treatments.

描述（由申请人提供）：该K99/R00提案的总体目标是进一步提高候选人在持续疼痛状况及其与抑郁症状共发病的免疫学基础方面的专业知识。更具体地说，该候选人寻求开发利用PET神经成像技术作为研究工具的专业知识，以了解免疫因子在慢性疼痛状态（如纤维肌痛（FM））的病理生理学中的作用。这样的研究很好地定位于发现慢性疼痛状态（如FM）中许多“身心”相互作用的机制。候选人所受的教育和训练使他为申请补助金做好了充分的准备。作为密歇根大学精神病学临床讲师，该候选人接受过工程师、精神病学家和PET神经成像师的培训，对炎症细胞因子在抑郁和疼痛状态中的作用有着不断发展的研究兴趣。因此，他很好地准备推进以病人为导向的心理神经免疫学研究。然而，为了实现完全的研究独立性并获得有竞争力的终身教职，他定义了需要进一步/补充培训的特定领域：1)慢性疼痛研究，2)先天免疫功能（增强实际细胞因子分析技能），3)先进统计技术，以及4)PET神经成像高级分析技术。环境：候选人将受益于密歇根大学精神病学和其他院系（即放射学、密歇根临床与健康研究所、统计咨询与研究中心）研究人员之间建立的合作关系。候选人可以使用PET和MRI扫描设备，细胞因子检测实验室和广泛的临床样本。候选人的主要导师Jon-Kar Zubieta博士在抑郁症和疼痛的PET神经成像方面拥有15年的专业知识，作为导师和富有成效的神经科学家，他已经有了良好的记录。另外还有两名内部导师。丹尼尔·克劳（疼痛）和艾丽莎·科赫（免疫学），以及一位外部导师史蒂文·扎尔曼博士（细胞因子挑战的行为后果）将组成指导团队。一名外部顾问（Andrew Miller博士）和两名内部顾问（Robert Koeppe博士和Edward Rothman博士）将分别就使用tnf - α拮抗剂（即依那西普）作为炎症挑战、PET神经成像物理和统计方法提供专家咨询。研究：跨越奖励期限，拟议的研究计划侧重于确定炎症细胞因子在慢性疼痛状态（即FM）病理生理中的作用。FM是一种常见的使人衰弱的疾病，也是一个重要的公共卫生问题。依那西普是一种细胞因子（即tnf - α）拮抗剂，在确定细胞因子在FM中枢mua -阿片受体介导的抗伤害机制失调中所起的作用时，被提出作为一种机制探针来区分因果关系和外因现象。目前对FM的生物学基础的理解以模棱两可的发现为标志。一些数据表明FM的潜在失调是中枢的，如mu-阿片受体介导的神经传递的下调，而其他数据表明涉及促炎细胞因子的外周伤害机制失调。初步数据表明，外周机制和中枢机制都参与其中，并进一步相互作用，可能使疼痛持续存在。事实上，在人类和动物模型中，促炎细胞因子（即tnf - α， il -1 β）与高痛觉性状态（即FM中的疼痛超敏性）有关。促炎细胞因子拮抗剂（即依那西普）在动物模型中已被证明可以逆转这种高度伤害性状态。然而，由于缺乏可用的研究范式来机械地揭示FM的基础，人体体内研究受到限制。初步数据显示，促炎细胞因子与疼痛状态、抑郁、疼痛和情绪应激反应中中枢mu-阿片样神经递质功能的激活和潜在失调有关。这些数据特别涉及腹侧纹状体和杏仁核，这些区域涉及编码显著和压力信号，奖励和厌恶信号。此外，这些数据暗示抗炎细胞因子（即IL-1ra，sTNF-alphaR1）在体内对这些相同区域的mu-阿片受体可用性具有相反的作用。然而，区分因果关系和外显现象是翻译成新的治疗策略的必要步骤。考虑到其直接和间接作用于风湿病过程中心的炎症细胞因子，以及细胞因子参与高痛觉状态和中枢阿片功能的数据