title: Nitroxyl inhibits overt pain-like behavior in mice: role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway.
abstract: BACKGROUND
  Several lines of evidence have indicated that nitric oxide (NO) plays complex and diverse roles in modulation of pain/analgesia. However, the roles of charged and uncharged congeners of NO are less well understood. In the present study, the antinociceptive effect of the nitroxyl (HNO) donor, Angeli's salt (Na2N2O3; AS) was investigated in models of overt pain-like behavior. Moreover, whether the antinociceptive effect of nitroxyl was dependent on the activation of cGMP (cyclic guanosine monophosphate)/PKG (protein kinase G)/ATP-sensitive potassium channels was addressed.
  
  
  METHODS
  The antinociceptive effect of AS was evaluated on phenyl-p-benzoquinone (PBQ)- and acetic acid-induced writhings and via the formalin test. In addition, pharmacological treatments targeting guanylate cyclase (ODQ), PKG (KT5923) and ATP-sensitive potassium channel (glybenclamide) were used.
  
  
  RESULTS
  PBQ and acetic acid induced significant writhing responses over 20min. The nociceptive response in these models were significantly reduced in a dose-dependent manner by subcutaneous pre-treatment with AS. Furthermore, AS also inhibited both phases of the formalin test. Subsequently, the inhibitory effect of AS in writhing and flinching responses were prevented by ODQ, KT5823 and glybenclamide, although these inhibitors alone did not alter the writhing score. Furthermore, pretreatment with L-cysteine, an HNO scavenger, confirmed that the antinociceptive effect of AS depends on HNO.
  
  
  CONCLUSIONS
  The present study demonstrates the efficacy of a nitroxyl donor and its analgesic mechanisms in overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channel (K(+)) signaling pathway.
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Staurengo-Ferrari
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
authors.forename: Daniela T
authors.initials: DT
authors.lastname: Longhi-Balbinot
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Marchesi
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: José C
authors.initials: JC
authors.lastname: Alves-Filho
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.affiliation: Department of Pharmaceutical Sciences, University Hospital (Health Science Centre), Londrina State University, Parana, Brazil.
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, USA.
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil. Electronic address: waverri@uel.br.
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D009589:Nitrogen Oxides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010147:Pain Measurement; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000700:Analgesics; D054086:KATP Channels; D009589:Nitrogen Oxides; D017869:Cyclic GMP-Dependent Protein Kinases; C039900:nitroxyl; D006152:Cyclic GMP
keywords: Angeli's salt; Formalin; Nitroxyl; Nociception; Pain