Chronic overlapping pain conditions (COPCs) affect over 100 million people, predominantly women. Yet, they
remain ineffectively treated due, in large part, to lack of valid animal models with translational relevance. In
response to FOA PAR-18-763, this proposal seeks to develop a new mouse model of COPCs with improved
external validity to facilitate discovery of neurotherapeutics with analgesic and anti-inflammatory effects. Our
model will incorporate key genetic and environmental factors known to contribute to the etiology of COPCs
through enhancing catacholaminergic tone. An estimated 66% of patients with COPCs such as fibromyalgia
have functional variants in the gene encoding catechol-O-methyltransferase (COMT; a ubiquitously expressed
enzyme that metabolizes catecholamines), that result in low COMT activity. The effect of COMT genotype on
pain is modified by stress and injury. For example, individuals with the ‘low activity’ COMT genotype report
enhanced pain following stressful events (eg, motor vehicle collision and psychological strain) and injurious
surgical procedures (eg, molar extraction and mastectomy). Low COMT, stress, and injury can produce pain by
increasing the production of pro-inflammatory cytokines that sensitize nociceptors. Previously, our lab
employed a pharmacologic approach to study mechanisms and targets driving COMT-dependent pain, yet this
approach does not adequately mimic the complex clinical etiology of COPCs. Thus, the objective of this
proposal is to develop and validate a novel mouse model of COPCS in which genetically predisposed
COMT+/- mice undergo stressful and injurious events. Our central hypothesis is that COMT+/- mice,
especially females, undergoing transient stressful and injurious events will develop chronic pain at multiple
body sites and increased levels of clinically-relevant cytokine biomarkers that will be reduced by existing FDA-
approved analgesics. Preliminary data show that COMT+/- mice, which exhibit normal baseline pain behavior,
undergoing swim stress and molar extraction surgery develop exaggerated long-lasting pain at multiple body
sites (hindpaw, back, and abdomen). Further, COMT+/- mice undergoing swim stress and molar extraction
exhibit increased nociceptor activity. The studies proposed herein will extend this work. During the 1.5-year
R61 phase, we will establish the magnitude and duration of pain at several body sites, sensitization of primary
afferent nociceptors innervating those body sites, and pain-related depressive- and anxiety-like behaviors in
our COPC mouse model. Upon meeting the ‘go milestones’: COMT+/- vs WT mice undergoing stress+injury
exhibit significant increases (effect size >3) in 1) mechanical pain at multiple body sites and 2) nociceptor
activity, we will move to the R33 phase. During the 1.5-year R33 phase, we will evaluate clinically-relevant
cytokine biomarkers to determine construct validity and clinically-used analgesics to determine predictive
validity of our model. If successful, we will develop a novel mouse model of COPCS with improved validity that
will have a significant impact on effective discovery of analgesics with translational relevance.