SUMMARY
Chronic inflammation affects millions of Americans each year and can manifest in a variety of chronic pain conditions
where normally innocuous stimuli produce pain symptoms. Long-term use of current pain therapeutics, including NSAIDS,
corticosteroids, and opioids, can cause unwanted side effects, and addiction potential can limit their utilization. Recent
studies have demonstrated a clear link between chronic low-grade inflammation and the increase in Chronic Inflammatory
Pain (CIP) conditions. Alternative therapeutic targets are needed for the treatment of these painful conditions. Nuclear
receptors, ligand-activated transcription factors that regulate a variety of physiological processes including metabolism,
inflammation, reproduction, and development, represent key drug discovery targets (second to GPCRs). The REV-ERB
proteins are nuclear receptors which function as transcriptional repressors and direct regulators of NLRP3 inflammasome
components and proinflammatory cytokines (IL-1¿, IL-18), and regulate the activity of macrophages at sites of cellular
damage. To date, the role of REV-ERB in relation to the manifestation of chronic pain symptoms has not been elucidated.
Due to its role in NLRP3 inflammasome and proinflammatory cytokine regulation, we hypothesize that REV-ERB is a
viable drug target for the treatment of inflammatory pain. Our strategy will leverage the known physiological functions of
REV-ERB in chronic inflammation and use a chemical biology approach to identify novel REV-ERB ligands, with superior
pharmacological profiles, to advance this potential therapy toward clinical trials. Our new preliminary data shows that total
loss of REV-ERB¿ in mice increases mechanical hypersensitivity. Our previous studies demonstrated that pharmacological
activation of REV-ERB had no negative effects in preclinical mouse reward models, suggesting that targeting of REV-ERB
may benefit many chronic pain conditions.