INVESTIGATION OF ADENOSINE IN THE PATHOGENESIS OF NONCARDIAC CHEST PAIN

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在美国，每年有超过30万的新患者被诊断为非心源性胸痛（NCCP），在他们的医疗保健上花费超过10亿美元。其病理生理机制尚不清楚，也没有被批准的治疗方法。这些研究者的独特研究已经证实，内脏痛觉过敏是NCCP的一个关键机制，疼痛与肌肉功能障碍无关。内脏痛觉过敏是一种涉及机械感受器和传入神经元的外周扰动，还是由于皮质加工异常，目前尚不清楚。情感脑、前扣带皮层（ACC）与思维脑、前额叶皮层（PFC）是否存在协同激活或这两个结构之间的分离尚不清楚。此外，内脏痛觉过敏的介质尚未被表征。最近，我们发现茶碱（一种腺苷受体拮抗剂）增加了NCCP的疼痛阈值，提示腺苷可能起作用。本方案将探讨腺苷、内脏痛觉过敏和脑-内脏轴在NCCP发病机制中的作用。具体目的是研究与接受安慰剂的受试者相比，接受腺苷治疗的健康受试者（目标1）和NCCP患者（目标2）是否表现出a)在食管球囊扩张过程中感知和疼痛阈值较低，b) PFC和ACC的激活增强。此外，这些研究人员将调查c)患者是否表现出比对照组更低的阈值和更大的皮层激活。目的3：他们假设茶碱预处理阻断了腺苷对胸痛的作用。方法：对20名健康受试者和20名NCCP患者进行目的1和目的2的检测。将对食管进行分级球囊扩张，以评估知觉和疼痛。同时，功能磁共振成像将评估皮质活动。接下来，受试者将随机接受腺苷或安慰剂输注，球囊扩张和功能磁共振成像将重复进行。为了测试Aim 3，他们将检查20名NCCP患者。患者将接受茶碱或安慰剂的预处理。接下来，在输注腺苷时进行球囊扩张。这个跨学科的项目应该为NCCP的发病机制提供有价值的机制见解，特别是腺苷和脑-内脏轴在介导胸痛中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Each year in the United States more than 300,000 new patients receive a diagnosis of noncardiac chest pain (NCCP) and more than $1 billion is spent on their health care. Its pathophysiology is poorly understood and there is no approved treatment. These investigators' unique studies have established that visceral hyperalgesia is a key mechanism for NCCP and pain is independent of muscle dysfunction. Whether visceral hyperalgesia is a peripheral perturbation involving mechanoreceptors and afferent neurons or due to abnormal cortical processing is unclear. Whether there is coactivation of the emotional brain, anterior cingulate cortex (ACC) and thinking brain, pre frontal cortex (PFC) or dissocation between these two structures is not known. Also, the mediators for visceral hyperalgesia have not been characterized. Recently, we have shown that theophyllin (an adenosine receptor antagonist) increases the thresholds for pain in NCCP, suggesting a possible role for adenosine. This protocol will investigate the role of adenosine, visceral hyperalgesia and brain-visceral axis in the pathogenesis of NCCP. The specific aims are to investigate if healthy subjects (Aim 1) and patients with NCCP (Aim 2) who receive adenosine, when compared to those who receive placebo demonstrate a) lower thresholds for perception and pain during esophageal balloon distention and b) enhanced activation of PFC and ACC. Also, these investigators will investigate c) if patients demonstrate lower thresholds and greater cortical activation than controls. Aim 3: They hypothesize that pretreatment with theophyllin blocks the effects of adenosine on chest pain. Methods: The investigators will examine 20 healthy subjects and 20 patients with NCCP for testing Aims 1 and 2. Graded balloon distentions of the esophagus will be performed to assess perception and pain. Simultaneously, fMRI will be performed to assess cortical activity. Next, subjects will be randomized to receive either adenosine or placebo infusion and balloon distention and fMRI will be repeated. For testing Aim 3, they will examine 20 patients with NCCP. patients will be pretreated with either theophyllin or placebo. Next, balloon distention will be performed during infusion of adenosine. This interdisciplinary project should provide valuable mechanistic insights regarding the pathogenesis of NCCP, in particular the role of adenosine and the brain-visceral axis in mediating chest pain.