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

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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.