title: Direct blockade of inflammatory hypernociception by peripheral A1 adenosine receptors: involvement of the NO/cGMP/PKG/KATP signaling pathway.
abstract: Through activation of the A1 adenosine receptors (A1Rs) at both the central and peripheral level, adenosine produces antinociception in a wide range of tests. However, the mechanisms involved in the peripheral effect are still not fully understood. Therefore, the mechanisms by which peripheral activation of A1Rs reduces inflammatory hypernociception (a decrease in the nociceptive threshold) were addressed in the present study. Immunofluorescence of rat dorsal root ganglion revealed significant expression of A1Rs in primary sensory neurons associated with nociceptive pathways. Functionally, peripheral activation of A1Rs reduced inflammatory hypernociception because intraplantar (i.pl.) administration of an A1R antagonist (DPCPX) enhanced carrageenan-induced hypernociception. On the other hand, local (paw) administration of CPA (a selective A1R agonist) reversed mechanical hypernociception induced by carrageenan or by the directly acting hypernociceptive mediator prostaglandin E(2) (PGE(2)). Down-regulation of A1Rs expression in primary nociceptive neurons by intrathecal treatment with antisense oligodeoxinucleotides significantly reduced peripheral antinociceptive action of CPA. Direct blockade of PGE(2) inflammatory hypernociception by the activation of A1Rs depends on the nitric oxide/cGMP/Protein Kinase G/KATP signaling pathway because the peripheral antinociceptive effect of CPA was prevented by pretreatment with inhibitors of neuronal nitric oxide synthase (N-propyl-l-arginine), guanylyl cyclase (ODQ), and Protein Kinase G (KT5823) as well as with a KATP blocker (glibenclamide). However, this effect of CPA was not reduced by naloxone, excluding the participation of endogenous opioids. These results suggest that the peripheral activation of A1R plays a role in the regulation of inflammatory hypernociception by a mechanism that involves the NO/cGMP/PKG/KATP intracellular signaling pathway.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto University of São Paulo, Avenida Bandeirantes, 3900, 14049-900 Ribeirão Preto, SP, Brazil Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, 86051-990 Londrina, PR, Brazil Biology Institute, State University of Campinas, UNICAMP, Campinas, São Paulo, Brazil.
authors.forename: Flávia Oliveira
authors.initials: FO
authors.lastname: Lima
authors.forename: Guilherme R
authors.initials: GR
authors.lastname: Souza
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Parada
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
mesh_terms: D058916:Adenosine A1 Receptor Antagonists / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D002351:Carrageenan / Q000009:adverse effects; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004333:Drug Administration Routes; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology; D050916:TRPV Cation Channels / Q000378:metabolism; D014970:Xanthines / Q000627:therapeutic use
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D004791:Enzyme Inhibitors; D054086:KATP Channels; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D043682:Receptor, Adenosine A1; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014970:Xanthines; D009569:Nitric Oxide; D002351:Carrageenan; C051360:1,3-dipropyl-8-cyclopentylxanthine; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; D015232:Dinoprostone
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