INVESTIGATION OF ADENOSINE IN THE PATHOGENESIS OF NONCARDIAC CHEST PAIN

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。在美国，每年有超过30万名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了超过10亿美元。其病理生理机制尚不清楚，目前还没有得到批准的治疗方法。这些研究人员的独特研究证实，内脏痛觉过敏是NCCP的关键机制，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干扰，还是由于皮质处理异常所致，目前尚不清楚。情绪脑、前扣带回皮质(ACC)和思考脑、前额叶皮质(PFC)或这两个结构之间是否存在共同激活尚不清楚。此外，内脏痛觉过敏的介体还没有确定。最近，我们发现茶碱(一种腺苷受体拮抗剂)提高了NCCP的痛阈值，提示腺苷可能起作用。该方案将探讨腺苷、内脏痛觉过敏和脑-内脏轴在NCCP发病机制中的作用。具体目的是调查服用腺苷的健康受试者(目标1)和NCCP患者(目标2)与接受安慰剂的患者相比，是否表现出a)在食道球囊扩张期间感觉和疼痛的阈值降低，以及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质激活。目的3：他们假设用茶碱预处理可阻断腺苷对胸痛的作用。方法：研究人员将检查20名健康受试者和20名NCCP患者，以测试目标1和2。分级球囊扩张食道将评估知觉和疼痛。同时，将进行功能磁共振成像以评估皮质活动。接下来，受试者将被随机接受腺苷或安慰剂注射，并重复球囊扩张和功能磁共振成像。为了测试目标3，他们将检查20名NCCP患者。患者将接受茶碱或安慰剂的预治疗。接下来，在输注腺苷的过程中将进行球囊扩张。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-内脏轴在调节胸痛中的作用。

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.