Plasmin contributes to arthritis pain by cleaving proteinase activated receptor-4 in rats

Proteinase activated receptors (PARs) are family of four G protein-coupled receptors that signal following enzymatic cleavage of their extracellular N-terminal domain. Activation of PAR-4 has been found to sensitize joint nociceptors leading to the generation of pain. The identity of the proteinases that activate PAR-4 in joints is unclear but may include the serine proteinase plasmin. The aim of this study was to determine whether plasmin signals joint pain via PAR-4 activation and whether the plasmin inhibitor neuroserpin could attenuate acute inflammatory joint pain. Either plasmin (0.04 - 04U) or vehicle (0.9% saline) were injected into the right knee joint of male rats and pain behaviour was assessed by von Frey hair mechanosensitivity or hindlimb dynamic weight bearing. Intra-articular injection of plasmin increased hindpaw mechanosensitivity and reduced the amount of weight borne on the ipsilateral hindlimb. These pain behaviours were attenuated by pre-treating the rats with the PAR-4 antagonist pepducin P4pal10 (100 μg i.p.) or the plasmin inhibitor neuroserpin (3 μg s.c.). In a group of animals with acute synovitis, prophylactic treatment with neuroserpin increased von Frey hair mechanical threshold but had no effect on weight bearing deficits. Taken together, these data show that plasmin produces joint pain by local activation of PAR-4 while blockade of plasmin bioactivity with neuroserpin can alleviate joint pain in an acute model of arthritis.