title: Peripheral mechanisms underlying the essential role of P2X3,2/3 receptors in the development of inflammatory hyperalgesia.
abstract: Activation of P2X3,2/3 receptors by endogenous ATP contributes to the development of inflammatory hyperalgesia. Given the clinical importance of mechanical hyperalgesia in inflammatory states, we hypothesized that the activation of P2X3,2/3 receptors by endogenous ATP contributes to carrageenan-induced mechanical hyperalgesia and that this contribution is mediated by an indirect and/or a direct sensitization of the primary afferent nociceptors. Co-administration of the selective P2X3,2/3 receptors antagonist A-317491, or the non-selective P2X3 receptor antagonist, TNP-ATP, with carrageenan blocked the mechanical hyperalgesia induced by carrageenan, and significantly reduced the increased concentration of tumor necrosis factor alpha (TNF-alpha) and chemokine-induced chemoattractant-1 (CINC-1) but not of interleukin-1 beta (IL-1 beta) induced by carrageenan. Co-administration of the selective P2X3,2/3 receptors antagonist A-317491 with carrageenan did not affect the neutrophil migration induced by carrageenan. Intrathecal administration of oligonucleotides antisense against P2X3 receptors for seven days significantly reduced the expression of P2X3 receptors in the saphenous nerve and significantly reduced the mechanical hyperalgesia induced by carrageenan. We concluded that the activation of P2X3,2/3 receptors by endogenous ATP is essential to the development of the mechanical hyperalgesia induced by carrageenan. Furthermore, we showed that this essential role of P2X3,2/3 receptors in the development of carrageenan-induced mechanical hyperalgesia is mediated by an indirect sensitization of the primary afferent nociceptors dependent on the previous release of TNF-alpha and by a direct sensitization of the primary afferent nociceptors.
authors.affiliation: Department of Physiological Sciences, Laboratory of Orofacial Pain, Piracicaba Dental School, State University of Campinas - UNICAMP, Brazil.
authors.forename: Maria Cláudia G
authors.initials: MC
authors.lastname: Oliveira
authors.forename: Adriana
authors.initials: A
authors.lastname: Pelegrini-da-Silva
authors.forename: Cláudia Herrera
authors.initials: CH
authors.lastname: Tambeli
authors.forename: Carlos Amílcar
authors.initials: CA
authors.lastname: Parada
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000031:analogs & derivatives; D000704:Analysis of Variance; D000818:Animals; D002351:Carrageenan; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004797:Enzyme-Linked Immunosorbent Assay; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D010636:Phenols / Q000008:administration & dosage; D011083:Polycyclic Compounds / Q000008:administration & dosage; D011134:Polysaccharides / Q000008:administration & dosage; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000737:chemistry / Q000502:physiology*; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; D013997:Time Factors
chemical_list: C470346:A-317491; D016207:Cytokines; D020319:Oligodeoxyribonucleotides, Antisense; D010636:Phenols; D011083:Polycyclic Compounds; D011134:Polysaccharides; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3; C045674:2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate; D000255:Adenosine Triphosphate; D002351:Carrageenan; C007789:fucoidan; D009195:Peroxidase