Mechanisms underlying TMD-IBS comorbidity

TMD-IBS 合并症的潜在机制

• 批准号: 8302493
• 负责人: RICHARD J Traub
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8302493
• 关键词: Abdominal Pain; Absence of pain sensation; Accounting; Address; Affect; Animal Model; Animals; Area; Attenuated; Brain; Categories; Chronic stress; Clinical; Colon; Colorectal; Comorbidity; Craniofacial Pain; Data; Defecation; Development; Diagnostic; Disease; Distal; Enteral; Estradiol; Estrogens; Failure; Female; Fibromyalgia; Future; Genetic; Goals; Gonadal Hormones; Habits; Hormonal; Hypersensitivity; Individual; Infection; Inflammation; Inflammatory; Injury; Intestines; Investigation; Irritable Bowel Syndrome; Location; Masseter Muscle; Menstrual cycle; Mental Depression; Modeling; Muscle; Myalgia; Nociception; Orofacial Pain; Pain; Pain Disorder; Pain intensity; Pain management; Pathway interactions; Patients; Perception; Peripheral; Persistent pain; Population; Posterior Horn Cells; Probability; Process; Psychological Factors; Rattus; Reporting; Risk; Role; Secondary Hyperalgesias; Sex Characteristics; Site; Spinal Cord; Stress; Stressful Event; Symptoms; Syndrome; System; Temporomandibular Joint Disorders; Testing; Tissues; United States; Up-Regulation; Visceral; Visceral pain; Woman; base; cell motility; central sensitization; chronic pain; cost; craniofacial; diffuse noxious inhibitory control; experience; falls; high reward; immune function; innovation; jaw movement; male; meetings; neurochemistry; response; temporomandibular pain

DESCRIPTION (provided by applicant): Functional chronic pain syndromes have no known pathophysiological basis yet affect millions of people in the United States. Many of these syndromes present as comorbid conditions. As many as 60% of patients with temporomandibular disorder (TMD) also report symptoms of abdominal pain consistent with irritable bowel syndrome (IBS), but the underlying connection between these comorbid conditions is unclear. There are some common clinical features, namely both conditions are substantially more common in women, the level of pain fluctuates during the menstrual cycle and they may be triggered or exacerbated by stress, but a mechanism that can connect these two conditions is unknown. The current application proposes a new animal model of comorbid pain conditions in which TMD and subchronic stress are combined to produce colonic hypersensitivity arising from otherwise healthy tissue. The longterm hypothesis is that persistent pain combined with stress alters the endogenous analgesia system resulting in enhanced secondary hyperalgesia in close proximity to the initial painful site, but also in hypersensitivityin distal deep tissue. The current application addresses the hypothesis that masseter muscle inflammation plus stress induces colonic hypersensitivity that is modulated by gonadal hormones. Furthermore, the visceral hypersensitivity results from central sensitization at the level of the spinal cord. This will be tested in two specific aims: Specific aim 1: Characterize a new model of comorbid pain conditions in which visceral hypersensitivity is induced by a combination of masseter muscle inflammation and subchronic stress. TMD and IBS are individually more prevalent in women and are sensitive to hormonal fluctuation during the menstrual cycle. In these individual animal models (masseter muscle inflammation, colorectal distention), females are more sensitive than males and estrogen increases sensitivity in ovariectomized rats. This aim will characterize the effects of estradiol on visceral and somatic sensitivity in the comorbidity model and test the hypothesis that the visceral hypersensitivity induced by the comorbid conditions is modulated by estradiol. Specific Aim 2: Determine if the visceral hypersensitivity in the comorbid pain model results from sensitization in the periphery or at the level of the spinal cord. As a first step in determining the underlying mechanisms that account for the increase in visceral sensitivity following injury plus stress we will determine if there are increases in neurochemical markers indicative of peripheral or central sensitization. Such changes will indicate that injury plus stress activates either a descending pathway or hormonal surge that sensitizes primary afferents and/or dorsal horn neurons. Failure to observe any neurochemical upregulation will support an alternative hypothesis that the visceral hypersensitivity results from sensitization of nociceptive processing above the level of the spinal cord. Either result will guide future studies into mechanisms underlying comorbid pain conditions. PUBLIC HEALTH RELEVANCE: Many functional chronic pain disorders occur in clusters of 2 or more conditions. Many patients report experiencing a stressful event prior to the onset of symptoms but this has not been proven causative. Additionally, being female tends to increase the probability of suffering from 1 or more functional pain syndromes. We have developed a model of a comorbid pain condition, temporomandibular pain plus stress inducing visceral hypersensitivity. Our long term goal is to determine the mechanisms underlying the development of pain from healthy tissue using this model. This will provide targets for better pain management. In this proposal we will determine the role of gonadal hormones in modulating pain intensity and determine if the visceral pain is due to central sensitization in the spinal cord.

描述（由申请人提供）：功能性慢性疼痛综合症尚无已知的病理生理基础，但影响了美国数百万的人。这些综合征中的许多是合并症。多达60％的颞下颌疾病（TMD）患者还报告了与肠易激综合征（IBS）一致的腹痛症状，但是这些合并症之间的潜在联系尚不清楚。有一些常见的临床特征，即两种疾病在女性中都更为普遍，在月经周期中的疼痛水平波动，并且可能会因压力而触发或加剧它们，但是一种可以连接这两种情况的机制尚不清楚。当前的应用提出了一种合并症疼痛条件的新动物模型，其中TMD和亚慢性应激被合并，以产生由健康的组织引起的结肠超敏反应。长期的假设是，持续性疼痛与压力结合改变了内源性镇痛系统，导致次级痛觉过敏增强，与最初的疼痛部位非常接近，但在远端深层组织中也是高度性的。当前的应用解决了以下假设：咬肌炎症和应激会诱导性腺激素调节的结肠超敏反应。此外，内脏超敏反应是由脊髓水平的中央敏化引起的。这将在两个特定的目标中进行测试：特定目标1：表征合并症的新模型，其中咬合肌肉炎症和亚少子应激的结合诱导内脏超敏反应。 TMD和IB在女性中单独更普遍，并且对月经周期中的激素波动敏感。在这些单个动物模型（咬肌炎症，结直肠差）中，女性比男性更敏感，雌激素会增加卵巢切除大鼠的敏感性。这个目标将表征雌二醇对合并症模型中内脏和体细胞敏感性的影响，并检验假设合并症诱导的内脏超敏反应是由雌二醇调节的。具体目标2：确定合并症模型中的内脏超敏反应是由外围敏化或 在脊髓的水平。作为确定损伤后内脏灵敏度增加的基本机制的第一步，我们将确定神经化学标记是否增加了外周或中心敏化的效果。这样的变化将表明损伤加压力激活降低的途径或激素激增，该途径使主要传入和/或背角神经元敏感。未能观察到任何神经化学上调将支持一种替代假设，即内脏超敏反应是由于对脊柱高于脊柱水平的伤害性处理的敏化而引起的 绳索。这两种结果将指导未来研究合并症疼痛条件的机制。 公共卫生相关性：许多功能性慢性疼痛障碍发生在2个或更多条件下。许多患者报告在症状发作之前经历了压力大事，但尚未证明这是病因。另外，女性倾向于增加患有1个或更多功能性疼痛综合征的痛苦的可能性。我们已经开发了合并症疼痛状况，颞下颌疼痛以及诱发内脏超敏反应的模型。我们的长期目标是使用该模型确定健康组织疼痛发展的基础机制。这将为更好的疼痛管理提供目标。在此提案中，我们将确定性腺激素在调节疼痛强度中的作用，并确定内脏疼痛是否是由于中心敏化引起的 脊髓。