Staurengo-Ferrari Larissa, Zarpelon Ana C, Longhi-Balbinot Daniela T, Marchesi Mario, Cunha Thiago M, Alves-Filho José C, Cunha Fernando Q, Ferreira Sergio H, Casagrande Rubia, Miranda Katrina M, Verri Waldiceu A
Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina, Brazil.
Department of Chemistry and Biochemistry, University of Arizona, Tucson, USA.
Pharmacol Rep. 2014 Aug;66(4):691-8. doi: 10.1016/j.pharep.2014.04.003. Epub 2014 Apr 22.
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.
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.
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.
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.
多项证据表明，一氧化氮（NO）在疼痛/镇痛调节中发挥着复杂多样的作用。然而，NO的带电和不带电同系物的作用尚不太清楚。在本研究中，我们在明显的疼痛样行为模型中研究了硝酰（HNO）供体安吉利盐（Na2N2O3；AS）的镇痛作用。此外，还探讨了硝酰的镇痛作用是否依赖于环磷酸鸟苷（cGMP）/蛋白激酶G（PKG）/ATP敏感性钾通道的激活。
通过苯醌（PBQ）和乙酸诱导的扭体反应以及福尔马林试验评估AS的镇痛作用。此外，还使用了针对鸟苷酸环化酶（ODQ）、PKG（KT5923）和ATP敏感性钾通道（格列本脲）的药物治疗。
PBQ和乙酸在20分钟内诱导出显著的扭体反应。皮下预处理AS可使这些模型中的伤害性反应以剂量依赖性方式显著降低。此外，AS还抑制了福尔马林试验的两个阶段。随后，ODQ、KT5823和格列本脲可阻断AS对扭体和退缩反应的抑制作用，尽管这些抑制剂单独使用时不会改变扭体评分。此外，HNO清除剂L-半胱氨酸预处理证实，AS的镇痛作用依赖于HNO。
本研究通过激活cGMP/PKG/ATP敏感性钾通道（K(+)）信号通路，证明了硝酰供体在明显的疼痛样行为中的疗效及其镇痛机制。
