Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Allardyce CS, Dyson PJ (2001) Ruthenium in medicine: current clinical uses and future prospects. Platin Met Rev 45:62–69

    CAS  Google Scholar 

  • Batinic-Haberle I, Cuzzocrea S, Reboucas JS, Ferrer-Sueta G, Mazzon E, Di Paola R, Radi R, Spsejevic I, Benov L, Salvemini D (2009) Pure MnTBAP selectively scavenges peroxynitrite over superoxide: comparison of pure and commercial MnTBAP samples to MnTE-2-PyP in two models of oxidative stress injury, an SOD-specific Escherichia coli model and carrageenan-induced pleurisy. Free Radic Biol Med 46(2):192–201

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bonaventura D, de Lima RG, Vercesi JA, da Silva RS, Bendhack LM (2007) Comparison of the mechanisms underlying the relaxation induced by two nitric oxide donors: sodium nitroprusside and a new ruthenium complex. Vasc Pharmacol 46:215–222

    Article  CAS  Google Scholar 

  • Borghi SM, Carvalho TT, Staurengo-Ferrari L, Hohmann MS, Pinge-Filho P, Casagrande R, Verri WA Jr (2013) Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. J Nat Prod 76(6):1141–1149

    Article  PubMed  CAS  Google Scholar 

  • Bradley PP, Priebat DA, Christensen RD, Rothstein G (1982) Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker. J Investig Dermatol 78(3):206–209

    Article  PubMed  CAS  Google Scholar 

  • Bredt DS, Hwang PM, Snyder SH (1990) Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 347:768–770

    Article  PubMed  CAS  Google Scholar 

  • Campelo MW, Oriá RB, Lopes LG, Brito GA, Santos AA, Vasconcelos RC, Silva FO, Nobrega BN, Bento-Silva MT, Vasconcelos PR (2012) Preconditioning with a novel metallopharmaceutical NO donor in anesthetized rats subjected to brain ischemia/reperfusion. Neurochem Res 37:749–758

    Article  PubMed  CAS  Google Scholar 

  • Casagrande R, Georgetti SR, Verri WA Jr, Dorta DJ, dos Santos AC, Fonseca MJ (2006) Protective effect of topical formulations containing quercetin against UVB-induced oxidative stress in hairless mice. J Photochem Photobiol B 84(1):21–27

    Article  PubMed  CAS  Google Scholar 

  • Chichorro JG, Lorenzetti BB, Zampronio AR (2004) Involvement of bradykinin, cytokines, sympathetic amines and prostaglandins in formalin-induced orofacial nociception in rats. Br J Pharmacol 141(7):1175–1184

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Clarke MJ, Zhu F, Frasca DR (1999) Non-platinum chemotherapeutic metallopharmaceuticals. Chem Rev 99:2511–2534

    Article  PubMed  CAS  Google Scholar 

  • Collier HO, Dinneen LC, Johnson CA, Schneider C (1968) The abdominal constriction response and its suppression by analgesic drugs in the mouse. Br J Pharmacol Chemother 32(2):295–310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cunha FQ, Poole S, Lorenzetti BB, Ferreira SH (1992) The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia. Br J Pharmacol 107:660–664

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cunha TM, Verri WA Jr, Vivancos GG, Moreira IF, Reis S, Parada CA et al (2004) An electronic pressure-meter nociception paw test for mice. Braz J Med Biol Res 37(3):401–407

    Article  PubMed  CAS  Google Scholar 

  • Cunha TM, Verri WA Jr, Silva JS, Poole S, Cunha FQ, Ferreira, SH (2005). A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc Natl Acad Sci USA 102(5):1755–1760

  • Cunha TM, Verri WA Jr, Schivo IR, Napimoga MH, Parada CA, Poole S, Teixeira MM, Ferreira SH, Cunha FQ (2008) Crucial role of neutrophils in the development of mechanical inflammatory hypernociception. J Leukoc Biol 83(4):824–832, Proc Natl Acad Sci USA 102(5):1755–60

    Article  PubMed  CAS  Google Scholar 

  • Cunha TM, Roman-Campos D, Lotufo CM, Duarte HL, Sousa GR, Verri WA Jr, Funez MI, Dias QM, Schivo IR, Domingues AC, Sachs D, Chiavegatto S, Teixeira MM, Hothersall JS, Cruz JS, Cunha FQ, Ferreira SH (2010) Morphine peripheral analgesia, depends on activation of the PI3Kgamma/AKT/nNOS/NO/KATP signaling pathway. Proc Natl Acad Sci U S A 107(9):4442–4447

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cunha TM, Sousa GR, Domingues AC, Carreira EU, Lotufo CM, Funez MI, Verri WA Jr, Cunha FQ, Ferreira SH (2012) Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3Kg/AKT/nNOS/NO signaling pathway. Mol Pain 8:10

  • Cury Y, Picolo G, Gutierrez VP, Ferreira SH (2011) Pain and analgesia: the dual effect of nitric oxide in the nociception system. Nitric Oxide 25:243–254

    Article  PubMed  CAS  Google Scholar 

  • Dal Secco D, Paron JA, de Oliveira SH, Ferreira SH, Silva JS, Cunha FQ (2003) Neutrophil migration in inflammation: nitric oxide inhibits rolling, adhesion and induces apoptosis. Nitric Oxide 9(3):153–164

    Article  PubMed  CAS  Google Scholar 

  • Dal Secco D, Moreira AP, Freitas A, Silva JS, Rossi MA, Ferreira SH, Cunha FQ (2006) Nitric oxide inhibits neutrophil migration by a mechanism dependent on ICAM-1: role of soluble guanylate cyclase. Nitric Oxide 15(1):77–86

    Article  PubMed  CAS  Google Scholar 

  • Diamantis AA, Dubrawski JV (1981) Preparation and structura of ethylenediaminetetraacetate complexes of ruthenium with dinitrogen, carbon monoxide, and other pi.-acceptor ligands. Inorg Chem 20(4):1142–1150

    Article  CAS  Google Scholar 

  • Dubuisson D, Dennis SG (1977) The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4(2):161–174

    Article  PubMed  CAS  Google Scholar 

  • Emele JF, Shanaman JE (1967) Analgesic activity of namoxyrate (2-[4-biphenylylbutyric acid 2-dimethylaminoethanol salt). Arch Int Pharmacodyn Ther 170(1):99–107

    PubMed  CAS  Google Scholar 

  • Finley A, Chen Z, Esposito E, Cuzzocrea S, Sabbadini R, Salvemini D (2013) Sphingosine 1-phosphate mediates hyperalgesia via a neutrophil-dependent mechanism. PloS One 8(1):e55255

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ford PC, Lorkovic IM (2002) Mechanistic aspects of the reactions of nitric oxide with transition–metal complexes. Chem Rev 102(4):993–1018

    Article  PubMed  CAS  Google Scholar 

  • Garthwaite J (1991) Glutamate, nitric oxide and cell-cell signaling in the nervous system. Trends Neurosci 14(2):60–67

    Article  PubMed  CAS  Google Scholar 

  • Garthwaite J (1995) Neural nitric oxide signaling. Trends Neurosci 1851–52

  • Gorbunov NV, Osipov AN, Day BW, Zayas-Rivera B, Kagan VE, Elsayed NM (1995) Reduction of ferrylmyoglobin and ferrylhemoglobin by nitric oxide: a protective mechanism against ferryl hemoprotein-induced oxidations. Biochemistry 34(20):6689–6699

    Article  PubMed  CAS  Google Scholar 

  • Guerrero AT, Verri WA Jr, Cunha TM, Silva TA, Schivo IR, Dal-Secco D, Canetti C, Rocha FA, Parada CA, Cunha FQ, Ferreira SH (2008) Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2. J Leukoc Biol 83(1):122–130

    Article  PubMed  CAS  Google Scholar 

  • Hattori H, Subramanian KK, Sakai J, Jia Y, Li Y, Luo HR (2010) Small-molecule screen identifies reactive oxygen species as key regulators of neutrophil chemotaxis. Proc Natl Acad Sci U S A 107(8):3546–3551

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Hibbs JB Jr, Taintor RR, Vavrin Z, Rachlin EM (1988) Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun 157(1):87–94

    Article  PubMed  CAS  Google Scholar 

  • Hickey MJ, Kubes P (1997) Role of nitric oxide in regulation of leucocyte–endothelial cell interactions. Exp Physiol 82(2):339–348

    PubMed  CAS  Google Scholar 

  • Hogg N, Kalyanaraman B (1999) Nitric oxide and lipid peroxidation. Biochim Biophys Acta 1411(2–3):378–384

    Article  PubMed  CAS  Google Scholar 

  • Hummel SG, Fischer AJ, Martin SM, Schafer FQ, Buettner GR (2006) Nitric oxide as a cellular antioxidant: a little goes a long way. Free Radic Biol Med 40(3):501–506

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Ignarro LJ (1989) Endothelium-derived nitric-oxide—actions and properties. FASEB J 3:31–36

    PubMed  CAS  Google Scholar 

  • Ignarro LJ (2000) Nitric oxide biology and pathobiology. Academic, New York, pp 3–19

    Book  Google Scholar 

  • Janes K, Neumann WL, Salvemini D (2012) Anti-superoxide and anti-peroxynitrite strategies in pain suppression. Biochim Biophys Acta 1822(5):815–821

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Keeble JE, Bodkin JV, Liang L, Wodarski R, Davies M, Fernandes ES, Coelho Cde F, Russell F, Graepel R, Muscara MN, Malcangio M, Brain SD (2009) Hydrogen peroxide is a novel mediator of inflammatory hyperalgesia, acting via transient receptor potential vanilloid 1-dependent and independent mechanisms. Pain 141:135–142

    Article  PubMed  CAS  Google Scholar 

  • Leite AC, Cunha FQ, Dal-Secco D, Fukada SY, Girão VC, Rocha FA (2009) Effects of nitric oxide on neutrophil influx depends on the tissue: role of leukotriene B4 and adhesion molecules. Br J Pharmacol 5:818–825

    Article  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 3(1):265–275

    Google Scholar 

  • Lu C, Koppenol WH (2005) Inhibition of the Fenton reaction by nitrogen monoxide. J Biol Inorg Chem 10(7):732–738

    Article  PubMed  CAS  Google Scholar 

  • Magro DA, Hohmann MS, Mizokami SS, Cunha TM, Alves-Filho JC, Casagrande R, Ferreira SH, Liew FY, Cunha FQ, Verri WA Jr (2013) An interleukin-33/ST2 signaling deficiency reduces overt pain-like behaviors in mice. Braz J Med Biol Res 46(7):601–606

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Maihöfner C, Euchenhofer C, Tegeder I, Beck KF, Pfeilschifter J, Geisslinger G (2000) Regulation and immunhistochemical localization of nitric oxide synthases and soluble guanylyl cyclase in mouse spinal cord following nociceptive stimulation. Neurosci Lett 290(1):71–75

    Article  PubMed  Google Scholar 

  • Marcondes FG, Ferro AA, Souza-Torsoni A, Sumitani M, Clarke MJ, Franco DW, Tfouni E, Krieger MH (2002) In vivo effects of the controlled NO donor/scavenger ruthenium cyclam complexes on blood pressure. Life Sci 70:2735–2752

    Article  PubMed  CAS  Google Scholar 

  • Matthews JR, Botting CH, Panico M, Morris HR, Hay RT (1996) Inhibition of NF–kappaB DNA binding by nitric oxide. Nucleic Acids Res 24(12):2236–2242

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • McCleverty JA (2004) Chemistry of nitric oxide relevant to biology. Chem Rev 104:403–418

    Article  PubMed  CAS  Google Scholar 

  • Mizokami SS, Arakawa NS, Ambrosio SR, Zarpelon AC, Casagrande R, Cunha TM, Ferreira SH, Cunha FQ, Verri WA Jr (2012) Kaurenoic acid from Sphagneticola trilobata inhibits inflammatory pain: effect on cytokine production and activation of the NO-cyclic GMP-protein kinase G-ATP-sensitive potassium channel signaling pathway. J Nat Prod 75(5):896–904

    Article  PubMed  CAS  Google Scholar 

  • Morris R, Southam E, Braid DJ, Garthwaite J (1992) Nitric oxide may act as a messenger between dorsal root ganglion neurones and their satellite cells. Neurosci Lett 137(1):29–32

    Article  PubMed  CAS  Google Scholar 

  • Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Palmer RM, Ashton DS, Moncada S (1988) Vascular endothelial cells synthesize nitric oxide from l-arginine. Nature 333:664–666

    Article  PubMed  CAS  Google Scholar 

  • Paula-Neto HA, Alves-Filho JC, Souto FO, Spiller F, Amêndola RS, Freitas A, Cunha FQ, Barja-Fidalgo C (2011) Inhibition of guanylyl cyclase restores neutrophil migration and maintains bactericidal activity increasing survival in sepsis. Shock 35(1):17–27

    Article  PubMed  CAS  Google Scholar 

  • Pavanelli WR, da Silva JJ, Panis C, Cunha TM, Costa IC, de Menezes MC, Oliveira FJ, Lopes LG, Cecchini R, Cunha Fde Q, Watanabe MA, Itano EN (2011) Experimental chemotherapy in paracoccidioidomycosis using ruthenium NO donor. Mycopathologia 172(2):95–107

    Article  PubMed  CAS  Google Scholar 

  • Pavao-de-Souza GF, Zarpelon AC, Tedeschi GC, Mizokami SS, Sanson JS, Cunha TM, Ferreira SH, Cunha FQ, Casagrande R, Verri WA Jr (2012) Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI(3)K and microglia in mice. Pharmacol Biochem Behav 101(3):320–328

    Article  PubMed  CAS  Google Scholar 

  • Pereira JCM, Carregaro V, Costa DL, da Silva JS, Cunha FQ, Franco DW (2010) Antileishmanial activity of ruthenium(II) tetraammine nitrosyl complexes. Eur J Med Chem 45:4180–4187

    Article  PubMed  Google Scholar 

  • Ribeiro RA, Vale ML, Thomazzi SM, Paschoalato AB, Poole S, Ferreira SH, Cunha FQ (2000). Involvement of resident macrophages and mast cells in the writhing nociceptive response induced by zymosanand acetic acid in mice. Eur J Pharmacol 387(1):111–118

  • Sachs D, Cunha FQ, Ferreira SH (2004) Peripheral analgesic blockade of hyperalgesia: activation of arginine/NO/cGMP/protein kinase G/ATP-sensitive K+ channel pathway. Proc Natl Acad Sci U S A 101(10):3680–3685

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Santodomingo-Garzon T, Cunha TM, Verri WA Jr, Valerio DA, Parada CA, Poole S, Ferreira SH, Cunha FQ (2006) Atorvastatin inhibits inflammatory hypernociception. Br J Pharmacol 49(1):14–22

    Article  Google Scholar 

  • Schmidtko A, Tegeder I, Geisslinger G (2009) No NO, no pain? The role of nitric oxide and cGMP in spinal pain processing. Trends Neurosci 32(6):339–346

    Article  PubMed  CAS  Google Scholar 

  • Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulphydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205

    Article  PubMed  CAS  Google Scholar 

  • Shi TJ, Holmberg K, Xu ZQ, Steinbusch H, de Vente J, Hökfelt T (1998) Effect of peripheral nerve injury on cGMP and nitric oxide synthase levels in rat dorsal root ganglia: time course and coexistence. Pain 78(3):171–180

    Article  PubMed  CAS  Google Scholar 

  • Sies H (1989) Biochemistry of thiol groups: the role of glutathione. Naturwissenschaften 76(2):57–64

    Article  PubMed  CAS  Google Scholar 

  • Silva JJ, Pavanelli WR, Pereira JC, Silva JS, Franco DW (2009) Experimental chemotherapy against Trypanosoma cruzi infection using ruthenium nitric oxide donors. Antimicrob Agents Chemother 53:4414–4421

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sousa AM, Prado WA (2001) The dual effect of a nitric oxide donor in nociception. Brain Res 897(1–2):9–19

    Article  PubMed  CAS  Google Scholar 

  • Staurengo-Ferrari L, Mizokami SS, Silva JJ, da Silva FO, Sousa EH, da França LG, Matuoka ML, Georgetti SR, Baracat MM, Casagrande R, Pavanelli WR, Verri WA Jr (2013) The ruthenium NO donor, [Ru(bpy)2(NO)SO3](PF6), inhibits inflammatory pain: involvement of TRPV1 and cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Pharmacol Biochem Behav 105:157–165

    Article  PubMed  CAS  Google Scholar 

  • Tfouni E, Truzzi DR, Tavares A, Gomes AJ, Figueiredo LE, Franco DW (2012) Biological activity of ruthenium nitrosyl complexes. Nitric Oxide 26(1):38–53

    Article  PubMed  CAS  Google Scholar 

  • Tonussi CR, Ferreira SH (1994) Mechanism of diclofenac analgesia: direct blockade of inflammatory sensitization. Eur J Pharmacol 251(2–3):173–179

    Article  PubMed  CAS  Google Scholar 

  • Vale ML, Rolim DE, Cavalcante IF, Ribeiro RA, Sousa MH (2007) Role of NO/cGMP/KATP pathway in antinociceptive effect of sildenafil in zymosan writhing response in mice. Inflamm Res 56(2):83–88

    Article  PubMed  CAS  Google Scholar 

  • Valerio DA, Cunha TM, Arakawa NS, Lemos HP, Da Costa FB, Parada CA, Ferreira SH, Cunha FQ, Verri WA (2007) Anti-inflammatory and analgesic effects of the sesquiterpene lactone budlein A in mice: inhibition of cytokine production-dependent mechanism. Eur J Pharmacol 562:155–163

    Article  PubMed  CAS  Google Scholar 

  • Valerio DA, Georgetti SR, Magro DA, Casagrande R, Cunha TM, Vicentini FT, Vieira SM, Fonseca MJ, Ferreira SH, Cunha FQ, Verri WA Jr (2009) Quercetin reduces inflammatory pain: inhibition of oxidative stress and cytokine production. J Nat Prod 72(11):1975–1979

    Article  PubMed  CAS  Google Scholar 

  • Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):1–40

    Article  PubMed  CAS  Google Scholar 

  • Verri WA Jr, Cunha TM, Parada CA, Poole S, Cunha FQ, Ferreira SH (2006a) Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther 112(1):116–138

    Article  PubMed  CAS  Google Scholar 

  • Verri WA Jr, Cunha TM, Parada CA, Wei XQ, Ferreira SH, Liew FY, Cunha FQ (2006b) IL-15 mediates immune inflammatory hypernociception by triggering a sequential release of IFN-gamma, endothelin, and prostaglandin. Proc Natl Acad Sci U S A 103:9721–9725

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Verri WA Jr, Cunha TM, Ferreira SH, Wei X, Leung BP, Fraser A, McInnes IB, Liew FY, Cunha FQ (2007) IL-15 mediates antigen-induced neutrophil migration by triggering IL-18 production. Eur J Immunol 37(12):3373–3380

    Article  PubMed  CAS  Google Scholar 

  • Verri WA Jr, Cunha TM, Magro DA, Domingues AC, Vieira SM, Sousa GR, Liew FY, Ferreira SH, Cunha FQ (2008) Role of IL-18 in overt pain-like behaviour in mice. Eur J Pharmacol 588(2–3):207–212

    Article  PubMed  CAS  Google Scholar 

  • Verri WA Jr, Cunha TM, Magro DA, Guerrero AT, Vieira SM, Carregaro V, Souza GR, Henriques M, Ferreira SH, Cunha FQ (2009) Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice. Naunyn Schmiedeberg’s Arch Pharmacol 3:271–279

    Article  Google Scholar 

  • Walley KR, McDonald TE, Higashimoto Y, Hayashi S. Modulation of proinflammatory cytokines by nitric oxide in murine acute lung injury (1999) Am J Respir Crit Care Med (2):698–704.

  • Wang ZQ, Porreca F, Cuzzocrea S, Galen K, Lightfoot R, Masini E, Muscoli C, Mollace V, Ndengele M, Ischiropoulos H, Salvemini D (2004) A newly identified role for superoxide in inflammatory pain. J Pharmacol Exp Ther 309(3):869–878

    Article  PubMed  CAS  Google Scholar 

  • Wieraszko A, Clarke MJ, Lang DR, Lopes LG, Franco DW (2001) The influence of NO containing ruthenium complexes on mouse hippocampal evoked potentials in vitro. Life Sci 68(13):1535–1544

    Article  PubMed  CAS  Google Scholar 

  • Wink DA, Mitchell JB (1998) Chemical biology of nitric oxide: insights into regulatory, cytotoxic, and cytoprotective mechanisms of nitric oxide. Free Radic Biol Med 25(4–5):434–456

    Article  PubMed  CAS  Google Scholar 

  • Xiong H, Zhu C, Li F, Hegazi R, He K, Babyatsky M, Bauer AJ, Plevy SE (2004) Inhibition of interleukin-12 p40 transcription and NF–κB activation by nitric oxide in murine macrophages and dendtritic cells. J Biol Chem 279:10776–10783

    Article  PubMed  CAS  Google Scholar 

  • Zanichelli PG, Miotto AM, Estrela HF, Soares FR, Grassi-Kassisse DM, Spadari-Bratfisch RC, Castellano EE, Roncaroli F, Parise AR, Olabe JA, de Brito AR, Franco DW (2004) The [Ru (HEDTA)NO](0.1-) system: structure, chemical reactivity and biological assays. J Inorg Biochem 98(11):1921–1932

    Article  PubMed  CAS  Google Scholar 

  • Zarpelon AC, Cunha TM, Alves-Filho JC, Pinto LG, Ferreira SH, McInnes IB, Xu D, Liew FY, Cunha FQ, Verri WA Jr (2013a) IL-33/ST2 signalling contributes to carrageenin-induced innate inflammation and inflammatory pain: role of cytokines, endothelin-1 and prostaglandin E2. Br J Pharmacol 169(1):90–101

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zarpelon AC, Souza GR, Cunha TM, Schivo IR, Marchesi M, Casagrande R, Pinge-Filho P, Cunha FQ, Ferreira SH, Miranda KM, Verri WA Jr (2013b) The nitroxyl donor, Angeli’s salt, inhibits inflammatory hyperalgesia in rats. Br J Pharmacol 71:1–9

    CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge the financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Departamento de Ciência e Tecnologia da Secretaria de Ciência, Tecnologia e Insumos Estratégicos and Ministério da Saúde (Decit/SCTIE/MS) by means of CNPq and support of SETI/Fundação Araucária and Paraná State Government. RC and WAVJ receive senior fellowship from CNPq and WRP receive senior fellowship from Fundação Araucaria.

Conflict of interest

The authors declare no conflict of interest.

Author information

Author notes

  1. Waldiceu A. Verri Jr.

    Present address: Departamento de Patologia, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM480 PR445, CEP 86057-970, Cx Postal 6001, Londrina, Paraná, Brazil

Authors and Affiliations

  1. 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

    Larissa Staurengo-Ferrari, Sandra S. Mizokami, Victor Fattori, Wander R. Pavanelli & Waldiceu A. Verri Jr.

  2. Universidade Estadual de Roraima, Rua Sete de Setembro, 231, Canarinho, CEP 69306-535, Boa Vista, Roraima, Brazil

    Jean J. Silva

  3. Instituto de Química de São Carlos, Universidade de São Paulo, São Paulo, Av. Trabalhador Sãocarlense, 400, CEP 13560-970, São Carlos, São Paulo, Brazil

    Patrícia G. Zanichelli

  4. Department of Pharmaceutical Sciences, Healthy Sciences Centre, Londrina State University, Av. Robert Koch, 60, CEP 86038-350, Londrina, Parana, Brazil

    Sandra R. Georgetti, Marcela M. Baracat & Rubia Casagrande

  5. Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Avenida da Universidade, 2853, CEP 60455-900, Fortaleza, Ceará, Brazil

    Luiz G. da França

Authors
  1. Larissa Staurengo-Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra S. Mizokami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor Fattori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean J. Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrícia G. Zanichelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sandra R. Georgetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Marcela M. Baracat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Luiz G. da França
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wander R. Pavanelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rubia Casagrande
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Waldiceu A. Verri Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Waldiceu A. Verri Jr..

Additional information

Larissa Staurengo-Ferrari, Sandra S. Mizokami and Victor Fattori contributed equally.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Staurengo-Ferrari, L., Mizokami, S.S., Fattori, V. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 387, 1053–1068 (2014). https://doi.org/10.1007/s00210-014-1030-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-014-1030-0

Keywords

Search

Navigation