Mechanisms Underlying Comorbid Pain Conditions in a Clinically Relevant Model

临床相关模型中共病疼痛的机制

基本信息

批准号：
9479287
负责人：
SUSAN G DORSEY
金额：
$ 49.68万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-04 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9479287
关键词：
Acute Affect Afferent Neurons Anatomy Animal Model Anxiety Attenuated Biochemical Blood Candidate Disease Gene Categories Characteristics Chronic Chronic Phase Chronic stress Colon Colorectal Comorbidity Corticotropin-Releasing Hormone Development Electrophysiology (science)Estrogens Etiology Fibromyalgia Functional disorder Genes Genetic Transcription Goals Hypersensitivity Inflammation Inflammation Mediators Injury Interstitial Cystitis Irritable Bowel Syndrome Masseter Muscle Measures Mediating Menstrual cycle Mental Depression Methodology Methods Modeling Muscle Neuraxis Neurons Ontology Pain Pain Disorder Pain management Pathology Pathway interactions Patients Peripheral Phase Posterior Horn Cells Rattus Reflex action Reporting Sensory Signal Pathway Signaling Protein Spinal Spinal Cord Spinal Ganglia Stress Swimming Symptoms Syndrome Temporomandibular Joint Disorders Testing Tissue-Specific Gene Expression Tissues United States Visceral Woman acute stress base central sensitization chronic pain chronic painful condition chronic pelvic pain clinically relevant cost differential expression dorsal horn experimental study gene product genetic signature insight mast cell model design novel therapeutics public health relevance recruit relating to nervous system

项目摘要

DESCRIPTION (provided by applicant): Chronic pain affects 100 million people in the United States at an annual cost surpassing $600 billion (2011 IOM report). Irritable bowel syndrome (IBS) and temporomandibular disorders (TMD) are functional chronic pain disorders of unknown etiology that are more prevalent in women, the pain fluctuates across the menstrual cycle, and the conditions are triggered/exacerbated by stress. The mechanisms underlying these conditions are not well understood so treatment options are poor. These conditions along with other functional pain syndromes overlap in presentation (>60% of TMD patients have IBS) further complicating pain management. A new experimental paradigm in rats models these comorbid pain conditions. Sub chronic stress induces transient visceral hypersensitivity that persists about 1 week. This new model of comorbid pain employs masseter muscle inflammation, modeling TMD, prior to the sub chronic stress to induce estrogen-dependent visceral hypersensitivity, modeling IBS. This comorbid visceral hypersensitivity persists months longer than the, transient visceral hypersensitivity induced by stress or masseter inflammation alone. Three specific aims will examine peripheral and spinal mechanisms that contribute to the acute (2 days) and chronic (1 month) phases of the comorbid visceral hypersensitivity. It is hypothesized that as the effects of the stress component of the acute/transient visceral hypersensitivity recede, there is a shift from peripheral to spinal mechanisms to maintain the chronic comorbid visceral hypersensitivity. Aim 1 will examine colonic afferent activity and the effects of peripheral CRF and mast cells in the acute and chronic phases. Aim 2 will examine changes in spinal visceroceptive neuron activity during the transition from acute to chronic pain. Aim 3 will test the hypothesis that unique gene signature sets, canonical and non-canonical signaling pathways and gene ontologies are enriched in anatomically relevant pain regions (colon, DRG, spinal cord) in the acute and chronic phases of comorbid visceral hypersensitivity. Successful completion of these specific aims will increase our understanding of mechanisms that contribute to the overlap of functional pain disorders, specifically TMD and IBS.

描述（由申请人提供）：慢性疼痛影响美国 1 亿人，每年造成的损失超过 6000 亿美元（IOM 2011 年报告）。肠易激综合征 (IBS) 和颞下颌关节紊乱病 (TMD) 是病因不明的功能性慢性疼痛疾病。这种情况在女性中更为普遍，疼痛在整个月经周期中波动，并且压力会引发/加剧这些症状。这些病症与其他功能性疼痛综合征的表现重叠（> 60% 的 TMD 患者患有 IBS），使大鼠模型中的疼痛管理模型进一步复杂化。慢性压力会诱发持续约 1 周的短暂内脏超敏反应。这种新的共病疼痛模型在亚慢性压力诱发雌激素依赖性内脏过敏之前，采用咬肌炎症来模拟 TMD。这种共存的内脏过敏症比单独由压力或咬肌炎症引起的短暂内脏过敏症持续时间更长，三个具体目标将检查导致急性（2 天）和慢性（1 个月）的外周和脊柱机制。共病内脏过敏的各个阶段被重新认识为急性/短暂内脏过敏的应激成分的影响。过敏消退，从外周机制转向脊髓机制以维持慢性共存内脏过敏。目标 1 将检查结肠传入活动，以及外周 CRF 和肥大细胞在急性和慢性阶段的影响。目标 3 将测试从急性疼痛过渡到慢性疼痛期间的内脏感受神经元活动，以检验独特的基因特征集、规范和非规范信号传导途径以及这一假设。基因本体在共病内脏过敏的急性和慢性阶段的解剖相关疼痛区域（结肠、DRG、脊髓）中丰富，成功完成这些特定目标将增加我们对导致功能性疼痛疾病重叠的机制的理解。特别是 TMD 和 IBS。