Gowler_2021_Arthritis.Rheumatol__

OBJECTIVE: Chronic pain due to osteoarthritis (OA) is a major clinical problem, existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous anti-inflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We hypothesized that sEH driven metabolism of the EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment. METHODS: Potential associations between chronic knee pain in people and single nucleotide polymorphisms (SNPs) in the gene encoding sEH and circulating levels of the EETs and DHETs were investigated. A surgically-induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of sEH by N-[1-(1-oxopropy)-4-piperidinyl]-N(') -(trifluoromethoxy)phenyl]urea (TPPU) on weight-bearing asymmetry, hind-paw withdrawal thresholds, joint histology, and circulating concentrations of the EETs and DHETs. RESULTS: In people with chronic knee pain, 3 pain measures were associated with SNPs of the sEH gene, EPHX2, and in two separate cohorts circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviours and decreased circulating levels of 8,9-DHET and 14,15-DHET. The levels of the EETs were unchanged by TPPU administration. CONCLUSION: Our novel findings support a role of sEH in OA pain and suggest that inhibition of sEH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.