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

NEUROPHARMACOLOGY

卷:71

Article

Zarpelon, Ana C.¹  Souza, Guilherme R.²  Cunha, Thiago M.²  Schivo, Ieda R. S.²  Marchesi, Mario³  Pinge-Filho, Phileno¹  Miranda, Katrina M.³  Verri, Waldiceu A., Jr.¹ 

[1] Univ Estadual Londrina, Ctr Ciencias Biol, Dept Patol, BR-86051990 Londrina, Parana, Brazil

[2] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP, Brazil

[3] Univ Arizona, Dept Chem & Biochem, Tucson, AZ USA

关键词: Nitroxyl;    Angeli's salt;    Nociception;    Pain;    Cytokine;    Nitric oxide;   

DOI  :  10.1016/j.neuropharm.2013.03.009

来源: Elsevier

【 摘 要 】

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 mu g/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-alpha, interleukin-1 beta and prostaglandin E-2. 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 OAF-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. (C) 2013 Elsevier Ltd. All rights reserved.

【 授权许可】

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