Physiological correlates of endogenous pain modulation in healthy individuals and

描述（由申请人提供）：本职业发展奖（K99/R00）的主要目标是为候选人提供保护时间，以获得必要的培训和指导，以建立一个独立的临床研究项目，了解疼痛调节的生理和心理机制，以及这些机制如何导致颞下颌关节紊乱（TMJD）。目前的提案扩展了候选人之前在压力和疼痛心理物理学方面的背景，并进行了额外的培训，以研究颞下颌关节痛病理生理学中涉及的生理和心理因素。K99指导阶段的特定培训领域将帮助候选人实现几个短期目标，包括在精神神经免疫学（PNI）、心理学理论和评估方面的专业知识，以及通过指导指导、教学课程和健康对照（HC）和颞下颌关节疾病患者的应用研究经验获得临床经验。此外，培训将提高候选人的工作效率，使其成为独立的临床研究人员，这将有助于获得终身教职和独立资金。培训的长期目标包括建立一个独立的研究实验室，以研究介导临床和实验疼痛的生理和心理因素。K99的指导阶段将在佛罗里达大学牙科学院进行，在Roger Fillingim博士和Joseph Riley博士的直接指导下，两位导师都是国内和国际上在疼痛和口腔面部研究领域备受尊敬的专家。环境非常适合这个项目，因为这所大学非常重视疼痛研究，包括口腔面部疼痛。候选人可以获得完成本提案中所述的一系列研究所需的必要实验室、设备和用品。本研究计划基于条件性疼痛调节（CPM）模型，开展一系列研究，旨在阐明内源性疼痛抑制TMJD患者疗效降低的介导因素。在这个模型中，疼痛抑制的特征是暴露于强直条件刺激时热痛敏感性的降低。虽然机制尚不清楚，但TMJD中疼痛抑制能力的降低可能是由于应激系统的不适应，该系统受到异常生理（即内源性阿片样物质，胆囊收缩素）和心理（即灾难化）对疼痛的反应的影响。本研究计划将利用职业规划期间发展的技能，研究适应不良的神经内分泌和促炎免疫反应以及负面心理反应作为TMJD疼痛抑制降低的重要因素的影响。这些观察将通过横断面评估（目的1）和疼痛预期的实验操作（目的2）来完成。候选人将使用在指导培训阶段（K99）获得的技能和知识过渡到独立（R00）阶段。目的3将研究内源性阿片类药物和胆囊收缩素系统与疼痛的心理和生物反应的相互作用。提出的一系列研究将为颞下颌关节痛患者的内源性疼痛调节提供更全面的了解。由于了解口腔面部疼痛的原因是国家牙科和颅面研究所（NIDCR）的目标，内源性疼痛抑制的机制是一个潜在的目标，可以帮助开发预防和治疗颞下颌关节痛的治疗方法。

DESCRIPTION (provided by applicant): The primary goal of this Career Development Award (K99/R00) is to provide protected time for the candidate to obtain the necessary training and mentoring to establish an independent clinical research program for understanding physiological and psychological mechanisms underlying pain modulation and how these mechanisms contribute to Temporomandibular Joint Disorder (TMJD). The current proposal extends the candidate's previous background in stress and pain psychophysics with additional training to investigate physiological and psychological factors involved in the pathophysiology of TMJD. Specific training areas in the mentored phase of the K99 will help the candidate achieve several short-term goals including developing expertise in psychoneuroimmunology (PNI), psychological theory and assessment, and clinical exposure through guided mentorship, didactic coursework, and applied research experiences in healthy controls (HC) and in patients with TMJD. In addition, the training will establish the candidate as an independent clinical researcher by increasing his productivity, which will assist in obtaining a tenure-track faculty position and independent funding. Long term goals of the training include establishing an independent research laboratory to investigate physiological and psychological factors mediating clinical and experimental pain. The mentored phase of the K99 will take place at the University of Florida College of Dentistry under the direct mentorship of Dr. Roger Fillingim, Ph.D. and co-mentorship of Dr. Joseph Riley, Ph.D., both mentors are nationally and internationally respected experts in the field of pain and orofacial research. The environment is ideal for this project because the university places a strong emphasis on pain research including orofacial pain. The necessary laboratory, equipment, and supplies needed to complete the series of studies described in this proposal are available to the candidate. The research plan offers a series of studies that are designed to elucidate factors mediating the reduced efficacy of endogenous pain inhibition TMJD patients based on a model of conditioned pain modulation (CPM). In this model, pain inhibition is characterized by a reduction of heat pain sensitivity during exposure to a tonic conditioning stimulus. While the mechanisms remain unknown, the reduced pain inhibitory capacity in TMJD could be due to a maladaptive stress system, which is influenced by abnormal physiological (i.e., endogenous opioids, cholecystokinin) and psychological (i.e., catastrophizing) responses to pain. The research plan will use the skills developed during the career plan to investigate the impact of maladaptive neuroendocrine and pro-inflammatory immune responses and negative psychological reactions as important factors in reduced pain inhibition in TMJD. These observations will be accomplished by cross-sectional evaluations (Aim 1) and experimental manipulations of pain expectation (Aim 2). The candidate will use the skills and knowledge gained during the mentored training phase (K99) to transition to the independent (R00) phase. Aim 3 will investigate the interactions of endogenous opioid and cholecystokinin systems with psychological and biological responses to pain. The proposed series of studies will provide a more thorough understanding of endogenous pain modulation in patients who suffer with TMJD. Since it is the goal of the National Institute of Dental and Craniofacial Research (NIDCR) to understand the causes of orofacial pain, the mechanisms underlying endogenous pain inhibition are a potential target that could assist in development of therapies to prevent and treat TMJD. PUBLIC HEALTH RELEVANCE: As a public health problem, TMJD is the most common chronic orofacial pain condition, associated with an overall negative impact on quality of life and a burden to our health care system. Current evidence regarding causes of TMJD is beginning to emerge, but additional research is needed. The current proposal addresses goals within the NIDCR strategic plan, which calls for studies that identify the causes and effects of orofacial pain, by enhancing our understanding of the mechanisms contributing to an imbalance in pain processing and modulation in TMJD patients.