title: Muscle hyperalgesia induced by peripheral P2X3 receptors is modulated by inflammatory mediators.
abstract: 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 α,β-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 β1- or β2-adrenoceptor antagonist atenolol and ICI 118,551, respectively. Also, the nonspecific selectin inhibitor fucoidan. α,β-meATP induced increases in the local concentration of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β), which were reduced by bradykinin antagonist. Finally, α,β-meATP also induced neutrophil migration. Together, these findings suggest that α,β-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.
authors.affiliation: Laboratory of Studies of Pain and Inflammation, School of Applied Sciences - UNICAMP, Limeira, Sao Paulo, Brazil; Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: J G
authors.initials: JG
authors.lastname: Schiavuzzo
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: J M
authors.initials: JM
authors.lastname: Teixeira
authors.affiliation: Laboratory of Studies of Pain and Inflammation, School of Applied Sciences - UNICAMP, Limeira, Sao Paulo, Brazil.
authors.forename: B
authors.initials: B
authors.lastname: Melo
authors.affiliation: Laboratory of Studies of Pain and Inflammation, School of Applied Sciences - UNICAMP, Limeira, Sao Paulo, Brazil.
authors.forename: D F
authors.initials: DF
authors.lastname: da Silva dos Santos
authors.affiliation: Laboratory of Studies of Pain and Inflammation, School of Applied Sciences - UNICAMP, Limeira, Sao Paulo, Brazil.
authors.forename: C O
authors.initials: CO
authors.lastname: Jorge
authors.affiliation: Laboratory of Studies of Pain and Inflammation, School of Applied Sciences - UNICAMP, Limeira, Sao Paulo, Brazil. Electronic address: maria.fusaro@fca.unicamp.br.
authors.forename: M C G
authors.initials: MC
authors.lastname: Oliveira-Fusaro
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas - UNICAMP, Campinas, Sao Paulo, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Parada
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000633:toxicity; D000588:Amines / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism* / Q000517:prevention & control; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism; D058911:Purinergic P2X Receptor Agonists / Q000633:toxicity*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000588:Amines; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D011453:Prostaglandins; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D043783:Receptor, Bradykinin B1; D011943:Receptors, Adrenergic, beta; D058477:Receptors, Purinergic P2X3; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D011451:Prostaglandin-Endoperoxide Synthases; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D001920:Bradykinin
keywords: P2X3 receptor; hyperalgesia; inflammatory mediators; muscle; α,β-meATP