title: The nitroxyl donor, Angeli's salt, inhibits inflammatory hyperalgesia in rats.
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; 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.
authors.affiliation: Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid PR 445, Km 380 Cx. Postal 6001, 86051-990 Londrina, Parana, Brazil.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Zarpelon
authors.forename: Guilherme R
authors.initials: GR
authors.lastname: Souza
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Cunha
authors.forename: Ieda R S
authors.initials: IR
authors.lastname: Schivo
authors.forename: Mario
authors.initials: M
authors.lastname: Marchesi
authors.forename: Rubia
authors.initials: R
authors.lastname: Casagrande
authors.forename: Phileno
authors.initials: P
authors.lastname: Pinge-Filho
authors.forename: Fernando Q
authors.initials: FQ
authors.lastname: Cunha
authors.forename: Sergio H
authors.initials: SH
authors.lastname: Ferreira
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Miranda
authors.forename: Waldiceu A
authors.initials: WA
authors.lastname: Verri
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006930:Hyperalgesia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009589:Nitrogen Oxides / Q000819:agonists* / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014110:Touch
chemical_list: D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D016166:Free Radical Scavengers; D020030:Nitric Oxide Donors; D009573:Nitrites; D009589:Nitrogen Oxides; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; C021229:oxyhyponitrite; C039900:nitroxyl
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