title: The ruthenium nitric oxide donor, [Ru(HEDTA)NO], inhibits acute nociception in mice by modulating oxidative stress, cytokine production and activating the cGMP/PKG/ATP-sensitive potassium channel signaling pathway.
abstract: Nitric oxide plays an important role in various biological processes including antinociception. The control of its local concentration is crucial for obtaining the desired effect and can be achieved with exogenous nitric oxide-carriers such as ruthenium complexes. Therefore, we evaluated the analgesic effect and mechanism of action of the ruthenium nitric oxide donor [Ru(HEDTA)NO] focusing on the role of cytokines, oxidative stress and activation of the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway. It was observed that [Ru(HEDTA)NO] inhibited in a dose-dependent (1-10 mg/kg) manner the acetic acid-induced writhing response. At the dose of 1 mg/kg, [Ru(HEDTA)NO] inhibited the phenyl-p-benzoquinone-induced writhing response, and formalin- and complete Freund's adjuvant-induced licking and flinching responses. Systemic and local treatments with [Ru(HEDTA)NO] also inhibited the carrageenin-induced mechanical hyperalgesia and increase of myeloperoxidase activity in paw skin samples. Mechanistically, [Ru(HEDTA)NO] inhibited carrageenin-induced production of the hyperalgesic cytokines tumor necrosis factor-α and interleukin-1β, and decrease of reduced glutathione levels. Furthermore, the inhibitory effect of [Ru(HEDTA)NO] in the carrageenin-induced hyperalgesia and myeloperoxidase activity was prevented by the treatment with ODQ (soluble guanylyl cyclase inhibitor), KT5823 (protein kinase G inhibitor) and glybenclamide (ATP-sensitive potassium channel inhibitor), indicating that [Ru(HEDTA)NO] inhibits inflammatory hyperalgesia by activating the cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway, respectively. These results demonstrate that [Ru(HEDTA)NO] exerts its analgesic effect in inflammation by inhibiting pro-nociceptive cytokine production, oxidative imbalance and activation of the nitric oxide/cyclic guanosine monophosphate/protein kinase G/ATP-sensitive potassium channel signaling pathway in mice.
authors.affiliation: Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 10.011, Londrina, Paraná, Brazil.
authors.forename: Larissa
authors.initials: L
authors.lastname: Staurengo-Ferrari
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Mizokami
authors.forename: Victor
authors.initials: V
authors.lastname: Fattori
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Silva
authors.forename: Patrícia G
authors.initials: PG
authors.lastname: Zanichelli
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Georgetti
authors.forename: Marcela M
authors.initials: MM
authors.lastname: Baracat
authors.forename: Luiz G
authors.initials: LG
authors.lastname: da França
authors.forename: Wander R
authors.initials: WR
authors.lastname: Pavanelli
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D017975:Ruthenium Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D054086:KATP Channels; D020030:Nitric Oxide Donors; D017975:Ruthenium Compounds; D009569:Nitric Oxide; D004492:Edetic Acid; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP; C026060:N-(hydroxyethyl)ethylenediaminetriacetic acid