A multi-target approach for pain treatment – dual inhibition of fatty acid amide hydrolase and TRPV1 in a rat model of osteoarthritis.

The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type-1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of osteoarthritis by 1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and 2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar DRG of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the DRG was observed. OMDM-198 showed anti-hyperalgesic effects in the osteoarthritis model, which were comparable to those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the non-pungent TRPV1 agonist, olvanil, suggesting its action as an “indirect” CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of osteoarthritis, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human osteoarthritis.