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首页> 外文期刊>The European Journal of Neuroscience >Inhibition of spinal constitutive NOS-2 by 1400W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation.
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Inhibition of spinal constitutive NOS-2 by 1400W attenuates tissue injury and inflammation-induced hyperalgesia and spinal p38 activation.

机译：1400W抑制脊髓组成型NOS-2可减轻组织损伤，炎症诱导的痛觉过敏和脊髓p38激活。

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Nitric oxide (NO) and its synthesizing enzymes, including NO synthase-2 (NOS-2, also called inducible NOS, iNOS), have been implicated in spinal nociception. 1400W is a highly selective NOS-2 inhibitor, as compared with either NOS-1 (neuronal NOS, nNOS) or NOS-3 (endothelial NOS). Here we examined the anti-nociceptive effects of intrathecal (IT) administration of 1400W in two experimental models of hyperalgesia (formalin and carrageenan models), in addition to the effect of 1400W on stimulation-induced activation of spinal p38 mitogen-activated protein kinase (p38). IT treatment of rats with 1400W produced a dose-dependent inhibition of paw formalin-induced phase II flinches, and attenuated carrageenan-induced thermal hyperalgesia. In contrast, IT injection of a selective inhibitor of NOS-1, nNOS inhibitor-I, had no effect in either model. Furthermore, 1400W at a dose that suppressed formalin-induced flinching behavior also blocked formalin-evoked p38 phosphorylation (activation) in the spinal cord, while nNOS inhibitor-I displayed no activity. The prompt effects of IT 1400W suggest involvement of constitutively expressed NOS-2 in spinal nociception. The NOS-2 protein in rat spinal cords was undetectable by Western blotting. However, when the protein was immunoprecipitated prior to Western blotting, NOS-2-immunoreactive bands were detected in the tissues, including naive spinal cords. The presence of constitutive spinal NOS-2 was further confirmed by reverse transcriptase-polymerase chain reaction. Taken together, the present studies suggest that constitutively expressed spinal NOS-2 mediates tissue injury and inflammation-induced hyperalgesia, and that activation of p38 is one of the downstream factors in NO-mediated signaling in the initial processing of spinal nociception.
机译：一氧化氮（NO）及其合成酶，包括NO合酶-2（NOS-2，也称为诱导型NOS，iNOS），已经牵涉到脊髓伤害感受中。与NOS-1（神经型NOS，nNOS）或NOS-3（内皮型NOS）相比，1400W是一种高度选择性的NOS-2抑制剂。在这里，我们研究了在两种痛觉过敏实验模型（福尔马林和角叉菜胶模型）中鞘内（IT）施用1400W的抗伤害感受作用，以及1400W对刺激诱导的脊髓p38促丝裂原活化蛋白激酶激活的镇痛作用（第38页）。 IT对1400W大鼠的治疗产生了剂量依赖性的爪福尔马林诱导的II期退缩，并减弱了角叉菜胶诱导的热痛觉过敏。相比之下，IT注射NOS-1选择性抑制剂nNOS抑制剂I在这两种模型中均无效。此外，在抑制福尔马林引起的退缩行为的剂量下1400W也阻断了脊髓中福尔马林诱发的p38磷酸化（激活），而nNOS抑制剂-I无活性。 IT 1400W的迅速作用表明，组成型表达的NOS-2参与了脊髓伤害感受。 Western印迹法检测不到大鼠脊髓中的NOS-2蛋白。但是，当蛋白质在Western印迹之前被免疫沉淀时，在包括幼稚脊髓在内的组织中检测到NOS-2-免疫反应带。通过逆转录酶-聚合酶链反应进一步证实了组成型脊髓NOS-2的存在。综上所述，本研究表明，组成型表达的脊髓NOS-2介导组织损伤和炎症诱导的痛觉过敏，并且p38的激活是脊髓伤害感受初始过程中NO介导的信号传导的下游因素之一。

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