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.

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.

• Authors: 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 Jr
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 66 Issue 4 Pg. 691-8 (Aug 2014) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 24948073 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. All rights reserved.

Chemical References

• Analgesics
• KATP Channels
• Nitrogen Oxides
• Cyclic GMP-Dependent Protein Kinases
• nitroxyl
• Cyclic GMP

Topics

• Analgesics (administration & dosage, pharmacology, therapeutic use)
• Animals
• Behavior, Animal (drug effects)
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• KATP Channels (metabolism)
• Male
• Mice
• Nitrogen Oxides (administration & dosage, pharmacology, therapeutic use)
• Pain (drug therapy, enzymology, metabolism)
• Pain Measurement
• Signal Transduction (drug effects)