The nitroxyl donor, Angeli's salt, inhibits inflammatory hyperalgesia in rats

Ana C. Zarpelon, Guilherme R. Souza, Thiago M. Cunha, Ieda R.S. Schivo, Mario Marchesi, Rubia Casagrande, Phileno Pinge-Filho, Fernando Q. Cunha, Sergio H. Ferreira, Katrina M. Miranda, Waldiceu A. Verri

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Nitric oxide modulates pain development. However, there is no evidence on the effect of nitroxyl (HNO/NO-) in nociception. Therefore, we addressed whether nitroxyl inhibits inflammatory hyperalgesia and its mechanism using the nitroxyl donor Angeli's salt (AS; Na2N2O 3). Mechanical hyperalgesia was evaluated using a modified Randall and Selitto method in rats, cytokine production by ELISA and nitroxyl was determined by confocal microscopy in DAF (a cell permeable reagent that is converted into a fluorescent molecule by nitrogen oxides)-treated dorsal root ganglia neurons in culture. Local pre-treatment with AS (17-450 μg/paw, 30 min) inhibited the carrageenin-induced mechanical hyperalgesia in a dose- and time-dependent manner with maximum inhibition of 97%. AS also inhibited carrageenin-induced cytokine production. AS inhibited the hyperalgesia induced by other inflammatory stimuli including lipopolysaccharide, tumor necrosis factor-α, interleukin-1β and prostaglandin E2. Furthermore, the analgesic effect of AS was prevented by treatment with ODQ (a soluble guanylate cyclase inhibitor), KT5823 (a protein kinase G [PKG] inhibitor) or glybenclamide (an ATP-sensitive K+ channel blocker), but not with naloxone (an opioid receptor antagonist). AS induced concentration-dependent increase in fluorescence intensity of DAF-treated neurons in a l-cysteine (nitroxyl scavenger) sensitive manner. l-cysteine did not affect the NO+ donor S-Nitroso-N-acetyl-DL- penicillamine (SNAP)-induced anti-hyperalgesia or fluorescence of DAF-treated neurons. This is the first study to demonstrate that nitroxyl inhibits inflammatory hyperalgesia by reducing cytokine production and activating the cGMP/PKG/ATP-sensitive K+ channel signaling pathway in vivo.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalNeuropharmacology
Volume71
DOIs
StatePublished - Aug 1 2013

Keywords

  • Angeli's salt
  • Cytokine
  • Nitric oxide
  • Nitroxyl
  • Nociception
  • Pain

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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  • Cite this

    Zarpelon, A. C., Souza, G. R., Cunha, T. M., Schivo, I. R. S., Marchesi, M., Casagrande, R., Pinge-Filho, P., Cunha, F. Q., Ferreira, S. H., Miranda, K. M., & Verri, W. A. (2013). The nitroxyl donor, Angeli's salt, inhibits inflammatory hyperalgesia in rats. Neuropharmacology, 71, 1-9. https://doi.org/10.1016/j.neuropharm.2013.03.009