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

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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.

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Acknowledgments

The authors thank the Central Microscopy Research Facility (CMRF) and Jessica Danielson, Sandra J. Kolker, and Lynn Rasmussen (University of Iowa, Iowa City, IA, USA) for technical assistance. This work was supported by Grants from Fundação de Amparo à Pesquisa do Estado de São Paulo - FAPESP, Brazil (2009/16854-3 and 2010/05381-4) and from National Institutes of Health - NIH, USA (AR053509, AR052316, and AR061371).

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Authors and Affiliations

  1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas (UNICAMP), Rua Monteiro Lobato, 255, Campinas, SP, CEP 13083-862, Brazil

    Juliana Maia Teixeira, Carlos Amílcar Parada & Cláudia Herrera Tambeli

  2. Department of Physiological Sciences, Center of Biological Sciences, Graduate Program in Neurosciences, Federal University of Santa Catarina (UFSC), Florianopolis, SC, Brazil

    Franciane Bobinski

  3. Department of Physical Therapy and Rehabilitation Science, Pain Research Program, The University of Iowa, Iowa City, IA, USA

    Kathleen A. Sluka

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  3. Carlos Amílcar Parada
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  4. Kathleen A. Sluka
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  5. Cláudia Herrera Tambeli
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Correspondence to Cláudia Herrera Tambeli.

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Teixeira, J.M., Bobinski, F., Parada, C.A. et al. P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis. Mol Neurobiol 54, 6174–6186 (2017). https://doi.org/10.1007/s12035-016-0146-2

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