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 propose an innovative multidisciplinary discovery-driven approach to identify novel targets for therapeutic intervention to treat these chronic pain conditions. We will use a recently reported rat model of comorbid pain hypersensitivity: masseter muscle inflammation followed by stress inducing de novo chronic visceral hypersensitivity, a defining characteristic of IBS. Combining visceral and orofacial pain measurement in awake animals, functional magnetic resonance imaging, mass spectrometry imaging of brain sections, and genetic and molecular approaches will allow identification of specific lipids and their metabolic pathways that change expression in the brain during the transition from acute to chronic overlapping pain. A longitudinal design will allow changes in brain activity in individual animals to be followed over weeks to months. In addition, areas of the brain that contribute to known sex differences in the magnitude and duration of the stress-induced and comorbid hypersensitivity should be identified. In three specific aims we will: 1) Identify changes in structure/function of brain regions in response to stress alone and pain plus stress which correlate with changes in visceral sensitivity and orofacial mechanosensitivity in male and female rats. Further, we will identify lipid moieties and the underlying metabolic pathways that change between baseline, acute and chronic pain conditions; 2) determine the effect of genetic knockdown of identified metabolic pathways in rat models of stress-induced and comorbid pain hypersensitivity. siRNA microinjected into brain regions identified in Aim 1 will be used to knockdown expression of enzymes that mediate the changes in lipid expression in the rat models. The effects of siRNA on the sensory and affective components of pain will be examined to help identify “drugable targets” for therapeutic intervention; and 3) Use pharmacological tools to test identified targets in order to confirm the clinical utility in reversing these conditions. The proposed studies will significantly advance understanding of chronic overlapping pain conditions and identify novel treatment targets.

Narrative Pain from Chronic Overlapping Pain Conditions is a pain management challenge for the physician and patient. This discovery-driven proposal will use multiple behavior and imaging techniques in an innovative longitudinal design to identify changes in brain activity and lipid neurochemistry in an animal model of chronic overlapping pain conditions. Combined with molecular and pharmacological approaches we will identify and validate novel targets for therapeutic intervention.