ICECAN

 描述（由申请人提供）：尽管NIH资助的间质性膀胱炎/膀胱疼痛综合征（IC/BPS）研究已持续25年，但尚未出现有意义的新疗法，病理生理学仍不清楚。IC/BPS使美国300万至800万女性遭受慢性疼痛、排尿功能障碍、睡眠剥夺和其他干扰人际关系和就业的共病状况，每年的成本超过1亿美元。我们已经组建了一个独特的团队，由具有不同专业知识的有成就的临床医生和科学家组成，涵盖临床骨盆疼痛，神经影像学，脑干连接，疼痛调节，自主神经疾病和心率变异性。基于ICEPAC研究（间质性膀胱炎-精神生理学和自主神经特征的阐明）的第一个周期结果，这项创新建议旨在了解纠正自主神经系统异常和潜在的大脑通路是否可以改变患有IC/BPS和肌筋膜骨盆疼痛综合征（MPP）的女性慢性骨盆疼痛的病程。ICEPAC先前的研究结果表明，这两种疾病在生理和心理上有所不同。然而，它们在临床上经常被混淆。ICEPAC发现，大多数女性同时患有这两种疾病，而大多数女性只有一种。然而，仔细的表型分析表明IC/BPS具有独特的自主特征，通过心率变异性测量自主神经系统反应性（ANS-R）降低。因此，目前的建议旨在确定ANS-R损伤是否可能导致IC/BPS及其症状。第一个目标是评估在IC/BPS和MPP受试者中，ANS-R的变化是否先于或跟随24周内疾病状态的变化。第二个目标将评估疾病状态如何响应于使用旨在通过降低交感神经紧张改善ANS-R的药物（β受体阻滞剂美托洛尔与安慰剂）直接修改ANS-R。我们期望更好的ANS-R改善IC/BPS的反应超过它改善MPP对标准治疗的反应。第三个目标将确定ANS-R的变化是否反映在大脑高级控制区域，前额叶皮层和导水管周围灰质之间的连接中，这是一个控制疼痛和自主功能的脑干开关，包括血压，心率和膀胱功能。我们预计，当IC/BPS改善时，更强的连接将反映更高的ANS-R。这项提议的创新之处在于：1）我们是第一个严格解析IC/BPS和MPP表型的小组，能够评估特定的疾病标志物; 2）这是第一个评估ANS-R在任何类型的慢性疼痛中的纵向前瞻性研究，以评估可能的因果关系。这项研究的发现可能为自主神经和疼痛通路的关系提供全新的见解。如果较差的ANS-R可能导致或维持慢性疼痛状态的假设被证明是正确的，那么慢性疼痛治疗的全新途径可能会打开，不仅在慢性盆腔疼痛中，而且在其他类型的疼痛中也是如此。重要的是，我们将对这些非常复杂的神经系统之间的相互作用有全新的认识。

 DESCRIPTION (provided by applicant): Despite 25 years of NIH funded investigation on interstitial cystitis/bladder pain syndrome (IC/BPS) focused on the bladder, no meaningful new therapies have emerged and the pathophysiology remains obscure. IC/BPS afflicts 3 to 8 million women in the US with chronic pain, voiding dysfunction, sleep deprivation and other co- morbid conditions that interfere with relationships and employment at a cost of over $100M/yr. We have assembled a unique group of accomplished clinicians and scientists with diverse expertise that spans clinical pelvic pain, neuroimaging, brainstem connectivity, pain modulation, autonomic disorders and heart rate variability across 3 sites. Based on the first cycle findings of the ICEPAC study (Interstitial Cystitis - Elucidation of Psychophysiologic and Autonomic Characteristics), this innovative proposal aims to understand whether correcting autonomic nervous system abnormalities and the underlying brain pathways can change the course of chronic pelvic pain in women suffering from IC/BPS and myofascial pelvic pain syndrome (MPP). Prior findings from ICEPAC showed that these two disorders differ in their physiology and psychology. Yet, they are often confused clinically. ICEPAC found that the majority of women have both disorders together, while a large minority has one. Careful phenotyping, however, demonstrates a unique autonomic profile for IC/BPS, with reduced autonomic nervous system responsiveness (ANS-R) measured by heart rate variability. The current proposal therefore aims to determine if ANS-R impairment may cause IC/BPS and its symptoms. The first aim will assess whether changes in ANS-R precede or follow changes in disease state over 24 weeks in subjects with IC/BPS and MPP. The second aim will evaluate how the disease state responds to direct modification of ANS-R using a medication intended to improve ANS-R by reducing sympathetic tone (the beta-blocker metroprolol vs placebo). We expect better ANS-R to improve response of IC/BPS more than it improves response of MPP to standard treatments. The third aim will determine whether ANS-R changes are reflected in connectivity between a high level control area in the brain, the prefrontal cortex, and the periaqueductal gray, a brainstem switch that controls pain and autonomic functions including blood pressure, heart rate and bladder function. We expect that stronger connections will reflect higher ANS-R when IC/BPS improves. This proposal is innovative in that 1) we are the first group to rigorously parse the phenotypes of IC/BPS and MPP, enabling assessment of specific disease markers; and 2) this is the first longitudinal prospective study assessing ANS-R in any type of chronic pain to assess possible causality. Findings from this study may provide entirely new insight into the relationship of autonomic and pain pathways. If the hypothesis that poor ANS-R may cause or maintain chronic pain states proves correct, entirely new avenues of chronic pain treatment may open, not just in chronic pelvic pain, but in other types of pain as well. Importantly, we would gain completely new insight into the interaction between these very complex neural systems.