Mechanisms Underlying Comorbid Pain Conditions in a Clinically Relevant Model

 描述(由申请人提供)：慢性疼痛影响着美国1亿人，每年的成本超过6000亿美元(2011年国际移民组织报告)。肠易激综合征(IBS)和颞下颌关节紊乱病(TMD)是一种病因不明的功能性慢性疼痛障碍，多见于女性，疼痛在月经周期中波动，由应激引发/加剧。这些情况背后的机制尚不清楚，因此治疗方案很差。这些情况与其他功能性疼痛综合征在表现上重叠(60%的TMD患者有IBS)，进一步使疼痛管理复杂化。一种新的实验范式在大鼠身上模拟了这些并存的疼痛状况。亚慢性应激导致一过性内脏高敏感性，持续约一周。这种新的共病疼痛模型采用咬肌炎症，模拟TMD，在亚慢性应激之前诱导雌激素依赖的内脏高敏感性，模拟IBS。这种并存的内脏高敏感症比单独由压力或咬肌炎症引起的短暂性内脏高敏症持续数月之久。三个特定的目标将检查外周和脊髓机制，有助于急性(2天)和慢性(1个月)的共病内脏过敏阶段。假设随着急性/短暂性内脏高敏感性的应力成分的影响消退，维持慢性共病内脏高敏感性的机制从外周机制转移到脊髓机制。目的1研究急性期和慢性期的结肠传入活动以及外周CRF和肥大细胞的作用。目的2将研究从急性疼痛到慢性疼痛过渡过程中脊髓内脏感觉神经元活性的变化。目的3将验证一种假说，即在共病的内脏高敏感性的急性期和慢性期，独特的基因信号集、规范和非规范的信号通路和基因本体论在解剖相关的疼痛区域(结肠、背根神经节、脊髓)中丰富。这些特定目标的成功完成将增加我们对导致功能性疼痛障碍重叠的机制的理解，特别是TMD和IBS。

 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.