Mechanisms Underlying Comorbid Pain Conditions in a Clinically Relevant Model

 描述（由申请人提供）：慢性疼痛影响美国1亿人，每年花费超过6000亿美元（2011年IOM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疾病，在女性中更为普遍，疼痛在月经周期中波动，并且这些病症由压力触发/加剧。这些疾病的潜在机制尚不清楚，因此治疗选择很差。这些病症沿着其他功能性疼痛综合征的表现重叠（>60%的TMD患者患有IBS），进一步使疼痛管理复杂化。一种新的实验范式在大鼠模型这些共病疼痛条件。亚慢性应激诱导持续约1周的短暂内脏高敏感性。这种新的共病疼痛模型采用咬肌炎症，模拟TMD，在亚慢性应激诱导雌激素依赖性内脏高敏感性，模拟IBS之前。这种共病的内脏高敏感性持续数月以上，短暂的内脏高敏感性引起的压力或咬肌炎症单独。三个具体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）阶段的共病内脏高敏感性。据推测，随着急性/一过性内脏高敏感性的应激成分的影响消退，从外周机制转移到脊髓机制，以维持慢性共病内脏高敏感性。目的1研究结肠传入活动及外周CRF和肥大细胞在急性期和慢性期的作用。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受神经元活动的变化。目的3将检验以下假设：在共病内脏高敏感性的急性和慢性阶段，独特的基因签名集、经典和非经典信号传导通路和基因本体在解剖学相关疼痛区域（结肠、DRG、脊髓）中富集。这些具体目标的成功完成将增加我们对功能性疼痛疾病重叠机制的理解，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.