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

• Published in: Neuropharmacology 2013-08, Vol.71, p.1-9
• Main Authors: Zarpelon, Ana C., Souza, Guilherme R., Cunha, Thiago M., Schivo, Ieda R.S., Marchesi, Mario, Casagrande, Rubia, Pinge-Filho, Phileno, Cunha, Fernando Q., Ferreira, Sergio H., Miranda, Katrina M., Verri, Waldiceu A.
• Format: Article
• Language: English
• Subjects: Analgesics, Non-Narcotic - administration & dosage; Analgesics, Non-Narcotic - antagonists & inhibitors; Analgesics, Non-Narcotic - pharmacology; Analgesics, Non-Narcotic - therapeutic use; Angeli's salt; Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - antagonists & inhibitors; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Cells, Cultured; Cytokine; Cytokines - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Free Radical Scavengers - pharmacology; Ganglia, Spinal - cytology; Ganglia, Spinal - drug effects; Ganglia, Spinal - immunology; Ganglia, Spinal - metabolism; Hyperalgesia - immunology; Hyperalgesia - metabolism; Hyperalgesia - prevention & control; Male; Neurons - cytology; Neurons - drug effects; Neurons - immunology; Neurons - metabolism; Nitric oxide; Nitric Oxide Donors - pharmacology; Nitrites - administration & dosage; Nitrites - antagonists & inhibitors; Nitrites - pharmacology; Nitrites - therapeutic use; Nitrogen Oxides - agonists; Nitrogen Oxides - antagonists & inhibitors; Nitroxyl; Nociception; Pain; Potassium Channel Blockers - pharmacology; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Wistar; Touch
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.03.009

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; Na2N2O3). 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. •Angeli's salt is a donor of HNO/NO−.•This is the first study showing the analgesic effect of HNO/NO− using Angeli's salt.•Angeli's salt inhibited the mechanical hyperalgesia induced by varied stimuli.•Its mechanisms include peripheral inhibition of cytokine production.•And activation of the cGMP/PKG/ATP-sensitive K+ channel signaling pathway.