title: P2X3 and P2X2/3 receptors mediate mechanical hyperalgesia induced by bradykinin, but not by pro-inflammatory cytokines, PGE₂ or dopamine.
abstract: 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.
authors.affiliation: 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
authors.forename: Maria Cláudia Gonçalves
authors.initials: MC
authors.lastname: de Oliveira Fusaro
authors.forename: Adriana
authors.initials: A
authors.lastname: Pelegrini-da-Silva
authors.forename: Dionéia
authors.initials: D
authors.lastname: Araldi
authors.forename: Carlos Amílcar
authors.initials: CA
authors.lastname: Parada
authors.forename: Cláudia Herrera
authors.initials: CH
authors.lastname: Tambeli
mesh_terms: 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
chemical_list: 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