P2X3 and P2X2/3 receptors mediate mechanical hyperalgesia induced by bradykinin, but not by pro-inflammatory cytokines, PGE₂ or dopamine.
Activation of peripheral P2X3 and P2X2/3 receptors by endogenous ATP is essential to the development of inflammatory hyperalgesia. We have previously demonstrated that this essential role of P2X3 and P2X2/3 receptors in the development of mechanical hyperalgesia induced by the inflammatory agent carrageenan is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of tumor necrosis factor alpha (TNF-α) and by a direct sensitization of the primary afferent nociceptors. Therefore, in this study we asked whether activation of P2X3 and P2X2/3 receptors contribute to the mechanical hyperalgesia induced by the inflammatory mediators involved in carrageenan-induced mechanical hyperalgesia, such as bradykinin, tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), chemokine-induced chemoattractant-1 (CINC-1), prostaglandin E₂ (PGE₂) and dopamine. Co-administration of the non-selective P2X3 receptor antagonist TNP-ATP or the selective P2X3 and P2X2/3 receptor antagonist A-317491 with bradykinin, but not with TNF-α, IL-1β, IL-6, CINC-1, PGE₂ or dopamine, prevented in a dose-dependent manner the mechanical hyperalgesia. We also verified whether the activation of P2X3 and P2X2/3 receptors by endogenous ATP contributes to bradykinin-induced mechanical hyperalgesia via neutrophil migration and/or cytokine release. Co-administration of TNP-ATP or A-317491 did not affect either neutrophil migration or the increased concentration of TNF-α, IL-1β, IL-6 and CINC-1 induced by bradykinin. These findings demonstrate that the activation of P2X3 and P2X2/3 receptors by endogenous ATP mediates bradykinin-induced mechanical hyperalgesia by a mechanism that does not depend on neutrophil migration or cytokines release.
de Oliveira Fusaro
Maria Cláudia Gonçalves
MC
Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas-UNICAMP, Limeira Av 901, 13414-900 Piracicaba, São Paulo, Brazil. oliveira_mcl@yahoo.com.br
Pelegrini-da-Silva
Adriana
A
Araldi
Dionéia
D
Parada
Carlos Amílcar
CA
Tambeli
Cláudia Herrera
CH
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects; D010147:Pain Measurement; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058476:Receptors, Purinergic P2X2 / Q000378:metabolism*; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D016207:Cytokines; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; D058920:Purinergic P2X Receptor Antagonists; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate; D015232:Dinoprostone; D001920:Bradykinin; D004298:Dopamine