title: Peripheral P2X7 receptor-induced mechanical hyperalgesia is mediated by bradykinin.
abstract: P2X7 receptors play an important role in inflammatory hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that P2X7 receptor activation induces mechanical hyperalgesia via the inflammatory mediators bradykinin, sympathomimetic amines, prostaglandin E2 (PGE2), and pro-inflammatory cytokines and via neutrophil migration in rats. We found that 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (BzATP), the most potent P2X7 receptor agonist available, induced a dose-dependent mechanical hyperalgesia that was blocked by the P2X7 receptor-selective antagonist A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist TNP-ATP. These findings confirm that, although BzATP also acts at both P2X1 and P2X3 receptors, BzATP-induced hyperalgesia was mediated only by P2X7 receptor activation. Co-administration of selective antagonists of bradykinin B1 (Des-Arg(8)-Leu(9)-BK (DALBK)) or B2 receptors (bradyzide), β1 (atenolol) or β2 adrenoceptors (ICI 118,551), or local pre-treatment with the cyclooxygenase inhibitor indomethacin or the nonspecific selectin inhibitor fucoidan each significantly reduced BzATP-induced mechanical hyperalgesia in the rat hind paw. BzATP also induced the release of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-6 and cytokine-induced neutrophil chemoattractant-1 (CINC-1), an effect that was significantly reduced by A-438079. Co-administration of DALBK or bradyzide with BzATP significantly reduced BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral P2X7 receptor activation induces mechanical hyperalgesia via inflammatory mediators, especially bradykinin, which may contribute to pro-inflammatory cytokine release. These pro-inflammatory cytokines in turn may mediate the contributions of PGE2, sympathomimetic amines and neutrophil migration to the mechanical hyperalgesia induced by local P2X7 receptor activation.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 255, Campinas, SP CEP 13083-862, Brazil.
authors.forename: J M
authors.initials: JM
authors.lastname: Teixeira
authors.affiliation: Faculty of Applied Sciences, State University of Campinas - UNICAMP, Rua Pedro Zaccaria, 1300, Limeira, SP CEP 13484-350, Brazil.
authors.forename: M C G
authors.initials: MC
authors.lastname: de Oliveira-Fusaro
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 255, Campinas, SP CEP 13083-862, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Parada
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Rua Monteiro Lobato, 255, Campinas, SP CEP 13083-862, Brazil. Electronic address: tambeli@unicamp.br.
authors.forename: C H
authors.initials: CH
authors.lastname: Tambeli
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D000818:Animals; D001920:Bradykinin / Q000378:metabolism*; D054360:Chemokine CXCL1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006614:Hindlimb; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D015213:Neuroimmunomodulation; D017208:Rats, Wistar; D058474:Receptors, Purinergic P2X1 / Q000378:metabolism; D058476:Receptors, Purinergic P2X2 / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D040521:Subcutaneous Tissue / Q000378:metabolism; D014110:Touch
chemical_list: D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D016207:Cytokines; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D058474:Receptors, Purinergic P2X1; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D001920:Bradykinin
keywords: BzATP; P2X7 receptor; inflammatory mediators; mechanical hyperalgesia; pro-inflammatory cytokines