Nitroxyl inhibits overt pain-like behavior in mice: Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway

Larissa Staurengo-Ferrari, Ana C. Zarpelon, Daniela T. Longhi-Balbinot, Mario Marchesi, Thiago M. Cunha, José C. Alves-Filho, Fernando Q. Cunha, Sergio H. Ferreira, Rubia Casagrande, Katrina M Miranda, Waldiceu A. Verri

Research output: Contribution to journalArticle

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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 20 min. 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. Conclusion 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.

Original languageEnglish (US)
Pages (from-to)691-698
Number of pages8
JournalPharmacological Reports
Volume66
Issue number4
DOIs
StatePublished - 2014

Fingerprint

KATP Channels
Cyclic GMP
Glyburide
Pain Measurement
Pain
Acetic Acid
Nitric Oxide
Cyclic GMP-Dependent Protein Kinases
Guanylate Cyclase
Analgesia
Cysteine
Analgesics
Pharmacology
Therapeutics
nitroxyl

Keywords

  • Angeli's salt
  • Formalin
  • Nitroxyl
  • Nociception
  • Pain

ASJC Scopus subject areas

  • Pharmacology
  • Medicine(all)

Cite this

Staurengo-Ferrari, L., Zarpelon, A. C., Longhi-Balbinot, D. T., Marchesi, M., Cunha, T. M., Alves-Filho, J. C., ... Verri, W. A. (2014). Nitroxyl inhibits overt pain-like behavior in mice: Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway. Pharmacological Reports, 66(4), 691-698. https://doi.org/10.1016/j.pharep.2014.04.003

Nitroxyl inhibits overt pain-like behavior in mice : Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway. / Staurengo-Ferrari, Larissa; Zarpelon, Ana C.; Longhi-Balbinot, Daniela T.; Marchesi, Mario; Cunha, Thiago M.; Alves-Filho, José C.; Cunha, Fernando Q.; Ferreira, Sergio H.; Casagrande, Rubia; Miranda, Katrina M; Verri, Waldiceu A.

In: Pharmacological Reports, Vol. 66, No. 4, 2014, p. 691-698.

Research output: Contribution to journalArticle

Staurengo-Ferrari, L, Zarpelon, AC, Longhi-Balbinot, DT, Marchesi, M, Cunha, TM, Alves-Filho, JC, Cunha, FQ, Ferreira, SH, Casagrande, R, Miranda, KM & Verri, WA 2014, 'Nitroxyl inhibits overt pain-like behavior in mice: Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway', Pharmacological Reports, vol. 66, no. 4, pp. 691-698. https://doi.org/10.1016/j.pharep.2014.04.003
Staurengo-Ferrari, Larissa ; Zarpelon, Ana C. ; Longhi-Balbinot, Daniela T. ; Marchesi, Mario ; Cunha, Thiago M. ; Alves-Filho, José C. ; Cunha, Fernando Q. ; Ferreira, Sergio H. ; Casagrande, Rubia ; Miranda, Katrina M ; Verri, Waldiceu A. / Nitroxyl inhibits overt pain-like behavior in mice : Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway. In: Pharmacological Reports. 2014 ; Vol. 66, No. 4. pp. 691-698.
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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 20 min. 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. Conclusion 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.",
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T1 - Nitroxyl inhibits overt pain-like behavior in mice

T2 - Role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway

AU - Staurengo-Ferrari, Larissa

AU - Zarpelon, Ana C.

AU - Longhi-Balbinot, Daniela T.

AU - Marchesi, Mario

AU - Cunha, Thiago M.

AU - Alves-Filho, José C.

AU - Cunha, Fernando Q.

AU - Ferreira, Sergio H.

AU - Casagrande, Rubia

AU - Miranda, Katrina M

AU - Verri, Waldiceu A.

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N2 - 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 20 min. 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. Conclusion 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.

AB - 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 20 min. 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. Conclusion 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.

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