A Novel Mouse Model of Chronic Primary Pain Conditions that Integrates Clinically Relevant Genetic and Environmental Factors

Abstract

Chronic primary pain conditions (CPPCs) 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. Here, we characterized a novel mouse model of CPPCs that integrated clinically-relevant genetic (catechol-o-methyltransferase; COMT knockdown) and environmental (stress and minor injury) factors. Compared to wildtype mice, COMT+/- mice undergoing the repeated swim stress and molar extraction surgery intervention exhibited pronounced multi-site body pain and depressive-like behavior lasting more than 3 months. The COMT+/- mice undergoing the intervention also exhibited enhanced activity of primary afferent DRG nociceptors innervating hindpaw and back sites and increased plasma levels of norepinephrine and the pro-inflammatory cytokines IL-6 and IL-17A. Notably, the pain and depressive-like behavior was of greater magnitude and longer duration (lasting at least 12 months) in females compared to males. Further, increases in anxiety-like behavior and IL-6 levels were female-specific. Intervention-induced body pain and nociception in COMT+/- mice was blocked by a beta-3 adrenergic antagonist, demonstrating predictive validity. Finally, the effect of COMT genotype x stress interactions on pain and IL-6 and IL-17A levels was observed in our clinical CPPC case-control cohort, demonstrating construct validity. Thus, our novel mouse model reliably recapitulates clinically- and biologically-relevant features of CPPCs and can be further implemented to test underlying mechanisms and discover new therapeutics. One Sentence SummaryWe developed a novel mouse model of chronic primary pain conditions that shares similar genetic, biologic, and clinical features of patients.