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

描述(由申请人提供)：这项K99/R00提案的首要目标是促进候选人在持续性疼痛状况及其与抑郁症状的共同发病率的免疫学基础上的专业知识。更具体地说，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，以了解免疫因素在纤维肌痛(FM)等慢性疼痛状态的病理生理中的作用。这样的研究很好地发现了像FM这样的慢性疼痛状态下许多“身心”相互作用的机制。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。作为密歇根大学精神病学的临床讲师，候选人接受过工程师、精神病学家和PET神经成像仪的培训，对炎症细胞因子在抑郁和疼痛状态中的作用具有不断发展的研究兴趣。因此，他做好了推进以患者为导向的心理神经免疫学研究的准备。然而，为了实现完全的研究独立性并获得具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(增强实用细胞因子分析技能)，3)高级统计技术，以及4)PET神经成像高级分析技术。环境：应聘者将受益于精神病学研究人员与密歇根大学其他系(即放射学、密歇根临床与健康研究所、统计咨询与研究中心)之间建立的合作关系。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、细胞因子分析实验室和多种临床样本。Jon-Kar Zubieta博士是候选人的主要导师，作为导师和富有成效的神经学家，他在抑郁症和疼痛的PET神经成像方面拥有15年的专业经验。另外两位内部导师Daniel Clauw博士(疼痛)和Alisa Koch博士(免疫学)，以及一位外部导师Steven Zalcman博士(细胞因子挑战的行为后果)将组成导师团队。一名外部顾问(安德鲁·米勒博士)和两名内部顾问(罗伯特·科佩博士和爱德华·罗斯曼博士)将分别就使用肿瘤坏死因子-α拮抗剂(即依那西普)作为炎症挑战、PET神经成像物理学和统计学方法提供专家咨询。研究：在整个获奖期间，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)的病理生理学中的作用。FM是一种常见的、使人衰弱的疾病，也是一个重大的公共卫生问题。依那西普是一种细胞因子(即肿瘤坏死因子-α)拮抗剂，被认为是区分因果关系和表观现象的机制探针，以确定细胞因子在中枢阿片受体介导的FM的抗伤害性反应机制中所起的作用。目前对FM的生物学基础的理解是模棱两可的发现。一些数据表明FM中潜在的失调是中枢的，例如Mu-阿片受体介导的神经传递下调，而另一些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，疼痛既涉及外周机制，也涉及中枢机制，并进一步相互作用，有可能使疼痛持续下去。事实上，在人类和动物模型中，促炎细胞因子(即，TNF-α、IL-1β)与高伤害性状态(即FM中的疼痛超敏)有关。促炎细胞因子拮抗剂(即依那西普)已经在动物模型中被证明可以逆转这种高度伤害性状态。然而，体内人类研究受到缺乏可用研究范式机械地解开FM的基础的限制。初步数据显示，在疼痛状态、抑郁以及对疼痛和情绪应激的反应中，促炎细胞因子与中枢阿片类神经递质功能的激活和潜在的失调有关。这些数据特别涉及腹侧纹状体和杏仁核，这两个区域涉及编码显著和应激信号、奖励和厌恶信号。此外，这些数据表明，抗炎细胞因子(即IL-1ra，sTNF-alphaR1)对这些相同区域的u-阿片受体在体内的可获得性具有相反的影响。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。考虑到它对风湿病过程中的炎性细胞因子的直接和间接作用，以及说明细胞因子参与高伤害性状态和中枢阿片类药物功能的数据 措施，依那西普非常适合这项任务。具体目的：目的1：确定慢性疼痛是否存在中度持续疼痛应激引起的中枢MOR介导的神经传递(和外周炎症状态)的改变。目的2：在FM中，较低的基线MOR BPND(和较高的促炎细胞因子浓度)将预测对依那西普的反应。摘要：这份K99/R00提案与美国国立卫生研究院的使命(PA-10-006：疼痛研究中的机制、模型、测量和管理)非常一致。该项目将为一名有前途的初级研究员提供必要的额外培训，以使他成为一名临床翻译精神神经免疫学家。同时，该项目将解决有关急性和慢性疼痛状态(如FM)的机制基础鲜为人知的重要的、可测试的问题。

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.