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

这项K99/R00提案的首要目标是促进候选人在免疫学方面的专业知识 持续性疼痛状况的基础及其与抑郁症状的共同发病率。更具体地说， 应聘者寻求发展利用PET神经成像技术的专业知识作为研究 了解免疫因素在慢性疼痛状态病理生理学中的作用的工具，如 纤维肌痛(FM)。这样的研究很好地发现了许多“心身”背后的机制。 在像FM这样的慢性疼痛状态下的相互作用。 候选人：到目前为止，候选人的教育和培训已经为他获得拟议的拨款做好了充分的准备。一个 密歇根大学精神病学临床讲师，候选人接受过工程师培训， 精神病学家和PET神经成像仪对炎性细胞因子在脑血管疾病中的作用的研究兴趣不断发展 抑郁和疼痛状态。因此，他准备好推动以患者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，并获得竞争激烈的终身教职轨道，教师 他明确了需要进一步/补充培训的具体领域：1)慢性疼痛研究，2) 先天免疫功能(增强实用细胞因子分析技能)，3)先进的统计技术，以及 4)PET神经成像先进的分析技术。环境：应聘者将受益于已建立的 安大略省大学精神病学研究人员与其他部门的合作关系 密歇根(即放射学，密歇根临床和卫生研究所，统计咨询中心 和研究)。应聘者可使用正电子发射计算机断层扫描和核磁共振成像扫描设备，细胞因子检测实验室，以及广泛的 临床样本的范围。候选人的主要导师乔恩-卡尔·祖别塔博士有一个既定的记录，即 既是导师又是富有成效的神经学家，在抑郁症的PET神经成像和 疼痛。另外两名内部导师Daniel Clauw博士(疼痛)和Alisa Koch博士(免疫学)和一名外部导师 导师Steven Zalcman博士(细胞因子挑战的行为后果)将完成导师指导 一队。一名外部医生(安德鲁·米勒博士)和两名内部医生(罗伯特·科普博士和爱德华·罗斯曼博士) 顾问，将提供使用肿瘤坏死因子拮抗剂(即依那西普)作为炎症性药物的专家咨询 Challenges、PET神经成像物理学和统计学方法。研究：跨越奖项 持续时间，拟议的研究计划侧重于确定炎性细胞因子在 慢性疼痛状态的病理生理学(即FM)。FM是一种常见的、使人衰弱的疾病，也是一种重要的公众 健康问题。依那西普是一种细胞因子(即肿瘤坏死因子)拮抗剂，被认为是一种机制探针，可用于 区分因果关系和表观现象确定细胞因子在细胞因子调控失调中的作用 中枢阿片受体介导FM的抗伤害性机制。对生物学的最新认识 FM的基础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，如阿片受体介导的神经传递下调，而其他数据表明 涉及促炎细胞因子的外周伤害性感受机制失调。初步数据 表明外周机制和中枢机制都参与了，并且进一步地，相互作用， 潜在地使疼痛的持久性永久化。事实上，促炎细胞因子(即肿瘤坏死因子、IL-1SS)是 在人类和动物模型中与高伤害感觉状态(即FM中的疼痛超敏)有关。支持- 炎症细胞因子拮抗剂(即依那西普)已在动物模型中被证明可以逆转这种高... 伤害性状态。然而，体内人体研究受到缺乏可用研究范式的限制 机械地拆解FM的基础。初步数据显示，促炎细胞因子 疼痛与中枢阿片类神经递质功能的激活和潜在的失调有关 状态、抑郁，以及对痛苦和情绪压力的反应。这些数据特别表明腹侧 纹状体和杏仁核，参与编码显著和应激信号，奖励和厌恶。 此外，这些数据表明，抗炎细胞因子(即IL-1ra，sTNF-？R1)对 ？-阿片受体在这些相同区域的体内可用性。然而，区分因果关系和表观-- 现象是转变为新的治疗策略的必要步骤。鉴于其直接和间接的行动 关于风湿病过程中的炎性细胞因子，以及细胞因子参与的数据 在过度伤害性状态和中枢阿片类药物功能测量中，依那西普非常适合这项任务。 具体目标： 目的1：确定中度持续性疼痛应激引起的中枢多器官功能的改变 慢性疼痛的中介神经传递(和外周炎症状态)。 目的2：证明较低的基线MOR BPND(和较高的促炎细胞因子浓度) 将在FM中预测依那西普预治疗的反应。 摘要：本K99/R00提案与NIH的任务(PA-10-006：机制、模型、 疼痛研究中的测量和管理)。该项目将为一名有前途的初级调查员提供 作为一名临床翻译，他需要接受额外的培训才能独立 心理神经免疫学家。同时，该项目将解决重要的、可测试的问题 对急性和慢性疼痛状态(如FM)的机制基础了解甚少。

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. One external (Dr. Andrew Miller) and two internal (Dr. Robert Koeppe and Dr. Edward Rothman) consultants, will provide expert consultation in using TNF-¿ 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-¿) 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 ¿-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 ¿-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-¿, IL-1ss) 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 ¿-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-¿R1) as having opposing effects on ¿-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.