MUSCLE HYPERALGESIA INDUCED BY PERIPHERAL P2X3 RECEPTORS IS MODULATED BY INFLAMMATORY MEDIATORS

ATP, via activation of P2X3 receptors, has been highlighted as a key target in inflammatory hyperalgesia. Therefore, the aim of this study was to confirm whether the activation of P2X3 receptors in the gastrocnemius muscle of rats induces mechanical muscle hyperalgesia and, if so, to analyze the involvement of the classical inflammatory mediators (bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines and neutrophil migration) in this response. Intramuscular administration of the non-selective P2X3 receptor agonist alpha,beta-meATP in the gastrocnemius muscle of rats induced mechanical muscle hyperalgesia, which, in turn, was prevented by the selective P2X3 and P2X2/3 receptors antagonist A-317491, the selective bradykinin B1-receptor antagonist Des-Arg9-[Leu8]-BK (DALBK), the cyclooxygenase inhibitor indomethacin, the beta(1)-or beta(2)-adrenoceptor antagonist atenolol and ICI 118,551, respectively. Also, the nonspecific selectin inhibitor fucoidan. alpha,beta-meATP induced increases in the local concentration of the proinflammatory cytokines tumor necrosis factor-a (TNF-alpha) and interleukin 1 beta (IL-1 beta), which were reduced by bradykinin antagonist. Finally, alpha,beta-meATP also induced neutrophil migration. Together, these findings suggest that alpha,beta-meATP induced mechanical hyperalgesia in the gastrocnemius muscle of rats via activation of peripheral P2X3 receptors, which involves bradykinin, prostaglandins, sympathetic amines, pro-inflammatory cytokines release and neutrophil migration. It is also indicated that bradykinin is the key modulator of the mechanical muscle hyperalgesia induced by P2X3 receptors. Therefore, we suggest that P2X3 receptors are important targets to control muscle inflammatory pain. (C) 2014 IBRO. Published by Elsevier Ltd. All rights reserved.