Suppression of joint pain in transient receptor potential vanilloid 4 knockout rats with monoiodoacetate-induced osteoarthritis

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Introduction:</jats:title> <jats:p>Transient receptor potential vanilloid 4 (TRPV4) modulates osteoarthritic (OA) pain in animal models. However, the pathophysiological function of TRPV4 in regulating OA pain remains poorly understood.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>We developed TRPV4-knockout (TRPV4-KO) rats and assessed the effects of <jats:italic toggle="yes">Trpv4</jats:italic> gene deficiency in a monoiodoacetate (MIA)-induced OA pain model (MIA rats) by examining pain-related behavior, pathological changes, and electrophysiological changes in dorsal root ganglion (DRG) neurons. The changes detected in TRPV4-KO rats were confirmed in wild-type rats using a TRPV4 antagonist.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>Transient receptor potential vanilloid 4–KO rats showed the same pain threshold as wild-type rats for thermal or pressure stimuli under normal conditions. <jats:italic toggle="yes">Trpv4</jats:italic> gene deletion did not suppress the development of osteoarthritis pathologically in MIA rats. However, the OA-related mechanical pain behaviors observed in MIA rats, including decreased grip strength, increased mechanical allodynia, and reduced weight-bearing on the ipsilateral side, were completely suppressed in TRPV4-KO rats. The DRG neurons in wild-type but not TRPV4-KO MIA rats were depolarized with increased action potentials. Transient receptor potential vanilloid 4 antagonist treatments recapitulated the effects of genetic <jats:italic toggle="yes">Trpv4</jats:italic> deletion.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>Transient receptor potential vanilloid 4 was sensitized in the DRG neurons of MIA rats and played a critical role in the development of OA pain. These results suggest that the inhibition of TRPV4 might be a novel potent analgesic strategy for treating OA pain.</jats:p> </jats:sec>