Effect of soluble epoxide hydrolase and cyclooxygenase inhibition on lameness and synovial fluid prostanoids in horses with experimentally induced radiocarpal synovitis

Abstract

Purpose: Concurrently, rather than separately, blocking production of pro-nociceptive and degradation of anti-nociceptive lipids might result in better control of inflammatory joint pain in horses. Methods: The effects cyclooxygenase (COX) and soluble epoxide hydrolase (sEH) inhibition on lameness and synovial fluid (SF) prostanoids were determined in horses with radiocarpal synovitis. Six healthy horses were administered the sEH inhibitor t-TUCB, the COX inhibitor phenylbutazone or their combination, all IV, concurrently with LPS (3 μg) into a radiocarpal joint in a randomized, crossover design. Investigators were blinded to treatment identity. Lameness was quantified as surrogate for joint pain using a validated wireless lameness sensor before and up to 48 hours after treatment. Concentrations of prostaglandin (PG)E2 and thromboxane (Tx)A2 in SF were determined with ELISA-based assays. Areas under the curves of lameness (AUC-lameness), PGE2 (AUC-PGE2) and TxA2 (AUC-TxA2) were calculated and analyzed with repeated measures ANOVA with p<0.05 considered significant. Data are mean±SD. Results: AUC-lameness with phenylbutazone (2 mg kg-1; 285±207 mm 48h-1) was significantly lower than with t-TUCB (1 mg kg-1; 498±82), but was lowest (91±35) with combined phenylbutazone (2 mg kg-1) and t-TUCB (0.3 mg kg-1). This combination was associated with significantly smaller AUC-PGE2 (3,609±2,311 pg ml-1 48h-1) in SF than phenylbutazone (20,614±10,023) or t-TUCB (13,911±7,380) separately. AUC-TxA2 was significantly smaller with inhibiting COX alone (17,375±5,476 pg ml-1 48h-1) or combined with sEH (22,645±15,112) compared to inhibiting sEH alone (103,066±75,407). Conclusions: Combined COX and sEH inhibition enhanced analgesia and better-controlled SF prostanoid response in horses with inflammatory joint pain than inhibiting each enzyme separately.