P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

Abstract

Osteoarthritis (OA) is a degenerative and progressive disease, characterized by cartilage breakdown and by synovial membrane inflammation, which results in disability, joint swelling and pain. The purinergic P2X3 and P2X2/3 receptors contribute to development of inflammatory hyperalgesia, participate in arthritis processes in the knee joint and are expressed in chondrocytes and nociceptive afferent fibers innervating the knee joint. In this study, we hypothesized that P2X3 and P2X2/3 receptors activation by endogenous ATP (adenosine 5′-triphosphate) induces articular hyperalgesia in the knee joint of male and female rats through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration. We found that the blockade of articular P2X3 and P2X2/3 receptors significantly attenuated carrageenan-induced hyperalgesia in the knee joint of male and estrus female rats in a similar manner. The carrageenan-induced knee joint inflammation increased the expression of P2X3 receptors in chondrocytes of articular cartilage. Further, the blockade of articular P2X3 and P2X2/3 receptors significantly reduced the increased concentration of TNF-α, IL-6 and CINC-1 and the neutrophil migration induced by carrageenan. These findings indicate that P2X3 and P2X2/3 receptors activation by endogenous ATP is essential to hyperalgesia development in the knee joint through an indirect sensitization of primary afferent nociceptors dependent on the previous release of pro-inflammatory cytokines and/or on neutrophil migration.

Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease?

“…Furthermore, a recent study shows the activation of pyroptosis in OA fibroblast‐like synoviocytes by ATP together with TLR‐4 ligands . Finally, ATP increases pain sensitivity (hyperalgesia) via binding to the purinergic P2X3 and P2X2/3 receptors .…”

Purinergic Signalling: Therapeutic Developments

“…ATP levels in knee synovial fluid of patients with OA are related to pain intensity ( Kumahashi et al, 2011 ). P2X3 and P2X2/3R play an important role in the development of articular hyperalgesia of arthritic joints ( Teixeira et al, 2016 ). In the long-term complications following total hip arthroplasty, different polymorphic variants of the P2X7R are associated with high or reduced periprosthetic osteolysis ( Mrazek et al, 2010 ).…”

Purinergic Regulation of Neutrophil Function

“…Chimeric mice demonstrate that P2Y 2 R is required in BM-derived cells for hepatic neutrophil infiltration and subsequent liver damage. Inhibition of P2X 3 R and P2X 2/3 R with a selective antagonist reduces rat neutrophil infiltration into stimulus-induced inflamed knee joints ( 53 ) but not skin and subcutaneous tissues ( 54 , 55 ). Similarly, P2X 7 R antagonism inhibits rat neutrophil infiltration into inflamed knee joints ( 56 ), but knockout of P2X 7 R has no effect on skin neutrophil infiltration ( 57 ).…”