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：
9120414
负责人：
SUSAN G DORSEY
金额：
$ 56.82万
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/9120414
关键词：
Acute Affect Afferent Neurons Animal Model Anxiety Attenuated Biochemical Blood Candidate Disease Gene Categories Cells Characteristics Chronic Chronic Phase Chronic stress Colon Colorectal Corticotropin-Releasing Hormone Development Electrophysiology (science)Estrogens Etiology Fibromyalgia Genes Goals Health 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 Process Rattus Reflex action Reporting Sensory Process 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 Work acute stress base central sensitization chronic pain chronic pelvic pain clinically relevant cost differential expression dorsal horn gene product genetic signature insight model design novel therapeutics relating to nervous system research study

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（适用提供）：慢性疼痛在美国影响1亿美元的1亿美元（2011年IOM报告）。肠易激综合征（IBS）和颞下颌疾病（TMD）是未知病因的功能性慢性疼痛疾病，在女性中更为普遍，在整个月经周期中的疼痛波动，并且疾病被压力触发/恶化。这些条件下的机制尚不清楚，因此治疗选择很差。这些疾病以及其他功能性疼痛综合征在介绍中重叠（> 60％的TMD患者具有IBS），使疼痛管理更加复杂。大鼠的新实验范式对这些合并症的疼痛条件进行了建模。亚慢性应激会诱导短暂的内脏超敏反应，大约1周。这种合并症疼痛员工的新模型咬合肌肉感染，对TMD进行建模，然后在降低了雌激素依赖性内脏超敏反应之前，对IBS进行了建模。这种合并的内脏超敏反应的持续数月比仅由应激或咬合者感染引起的短暂性内脏超敏反应。三个具体目标将检查有助于合并内脏超敏反应的急性（2天）和慢性（1个月）阶段的外围和脊柱机制。众所周知，作为急性/瞬态内脏超敏反应接收的应力成分的影响，从周围的脊柱机制发生了转变，以维持慢性合并性内脏超敏反应。 AIM 1将检查结肠传入活性以及急性和慢性阶段中周围CRF和肥大细胞的影响。 AIM 2将检查从急性到慢性疼痛的过渡过程中脊柱感知性神经元活性的变化。 AIM 3将检验以下假设：在共肽内粘性高敏性的急性和慢性阶段中，独特的基因特征集，规范和非传统信号通路和基因本体学富含解剖学相关的疼痛区域（结肠，DRG，脊髓）。这些特定目标的成功完成将增加我们对有助于功能性疼痛障碍（特别是TMD和IBS）重叠的机制的理解。