Novel target identification for treatment of chronic overlapping pain using multimodal brain imaging

总结 慢性重叠性疼痛病症（COPC）是具有最小可识别的疼痛症状的特发性疼痛病症。 起源于器质性疾病，代表了医生和 病人它们发生在数千万美国人身上，每年花费超过1000亿美元。流行病学 数据表明，这些疾病中的许多在同一患者中的表现重叠， 超过50%的条件。通常身体的空间分离区域受到影响（例如， 颞下颌关节紊乱病（TMD）和肠易激综合征（IBS）），这强烈表明， 涉及中枢神经系统机制。此外，压力触发或加剧了许多这些 条件，这更频繁地发生或专门在妇女。不同的痛苦汇聚在一起 周围组织和感知压力最可能发生在大脑中。我们已经建立了一个动物模型， 涉及咬肌炎症和应激的共病疼痛状况，以诱导慢性内脏 超敏反应模拟TMD和IBS患者的疼痛。本补充项目的目的是 完善这种共病疼痛模型，以进一步用于我们的新型治疗靶点发现项目。我们提出了一个 更自然的口面条件，错牙合产生单侧前牙反牙合，这已经被 引起颞下颌关节疼痛这将与侵入性较小的方法相结合， 内脏高敏感性，使用牵涉性疼痛而不是内脏反应，消除了对 手术植入电极和单个外壳以保护电极导线免受笼状体的影响。这些条件 提出了改进模型更接近的条件，可能有助于慢性 重叠疼痛，以获得机制的理解和帮助发现新的治疗靶点。

Summary Chronic overlapping pain conditions (COPCs) are idiopathic pain conditions that have minimal identifiable origins in organic disease and represent a highly significant pain management challenge for physician and patient. They occur in tens of millions of Americans with annual costs exceeding $100 billion. Epidemiological data indicate many of these conditions overlap in presentation in the same patient, with odds of presenting 2 or more conditions exceeding 50%. Often spatially separate areas of the body are affected (e.g., temporomandibular disorder (TMD) and irritable bowel syndrome (IBS)), which strongly suggests the involvement of central nervous system mechanisms. Additionally, stress triggers or exacerbates many of these conditions, which occur more frequently or exclusively in women. The convergence of pain from different peripheral tissues and perceived stress most likely occurs in the brain. We have developed an animal model of comorbid pain conditions that involves masseter muscle inflammation plus stress to induce chronic visceral hypersensitivity modeling the pain in patients with TMD and IBS. The purpose of this supplemental project is to refine this comorbid pain model for further use in our novel therapeutic target discovery project. We propose a more natural orofacial condition, malocclusion producing a unilateral anterior crossbite, which has been reported to evoke temporomandibular joint pain. This will be combined with less invasive methods to measure visceral hypersensitivity, using referred pain rather than the visceromotor response, eliminating the need for surgery to implant electrodes and single housing to protect electrode leads from cagemates. These conditions are proposed to refine the model more closely approximating conditions that might contribute to chronic overlapping pain in order to gain a mechanistic understanding and aid discovery of novel therapeutic targets.