Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase
Intact carrageenan-induced thermal hyperalgesia in mice lacking inducible nitric oxide synthase
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DOI：
10.1016/s0306-4522(03)00362-2
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发表时间：
2003-01-01
期刊：
影响因子：
3.3
通讯作者：
Johns, RA
中科院分区：
文献类型：
--
作者：
Tao, F;Tao, YX;Johns, RA
迄今为止，诱导型一氧化氮合酶（iNOS）在炎症性疼痛中的确切作用仍存在争议。在本研究中，我们结合了药理学策略（使用选择性iNOS抑制剂）和基因组策略（使用缺乏iNOS基因的小鼠）来解决iNOS在卡拉胶诱导的持续性炎症性疼痛的中心机制中的功能。在野生型小鼠中，鞘内给予L-N-（1-亚氨基乙基）赖氨酸，一种选择性的iNOS抑制剂，在卡拉胶炎症的晚期明显抑制热痛觉过敏，但在早期没有。后爪注射角叉菜胶后24 h（后期）显著诱导脊髓腰椎增大节段iNOS mRNA表达。有趣的是，iNOS基因的靶向破坏在早期（2-6 h）或晚期都不会影响卡拉胶诱导的热痛觉过敏。在iNOS敲除小鼠腰椎增大节段，注射角叉菜胶后24 h，一氧化氮合酶（NOS）酶活性维持在与野生型小鼠相似的水平。我们发现，鞘内给予7-硝基茚唑（一种选择性神经元NOS抑制剂），而不是L-N-（1-亚氨基乙基）鸟氨酸（一种选择性内皮NOS抑制剂），可显著减少iNOS敲除小鼠早期和晚期卡拉胶诱导的热痛觉过敏。我们还发现，与野生型小鼠相比，注射角叉菜胶后24小时，iNOS敲除小鼠腰大节段神经元NOS的表达明显增加，而内皮细胞NOS的表达不明显。我们的研究结果表明，神经元NOS可能在iNOS敲除小鼠角叉菜胶诱导的炎性疼痛后期补偿iNOS的功能。这表明，在卡拉胶诱导的热痛觉过敏后期，iNOS可能是充分的，但不是必需的。(c) 2003年。Elsevier Science Ltd.出版。版权所有。
To date, the exact role of inducible nitric oxide synthase (iNOS) in inflammatory pain remains controversial. In the present study, we combined a pharmacological strategy (using a selective iNOS inhibitor) with a genomic strategy (using mice lacking the iNOS gene) to address the function of iNOS in the central mechanism of carrageenan-induced persistent inflammatory pain. In the wild type mice, intrathecal administration of L-N-(1-iminoethyl)-lysine, a selective iNOS inhibitor, significantly inhibited thermal hyperalgesia in the late phase but not in the early phase of carrageenan inflammation. Moreover, iNOS mRNA expression in the lumbar enlargement segments of the spinal cord was dramatically induced at 24 h (late phase) after injection of carrageenan into a hind paw. Interestingly, targeted disruption of iNOS gene did not affect carrageenan-induced thermal hyperalgesia in either the early (2-6 h) or late phase. In the lumbar enlargement segments of iNOS knockout mice, nitric oxide synthase (NOS) enzyme activity remained at a similar level to that of the wild type mice at 24 h after carrageenan injection. We found that intrathecal administration of 7-nitroindazole (a selective neuronal NOS inhibitor), but not L-N-(1-iminoethyl)ornithine (a selective endothelial NOS inhibitor), significantly reduced carrageenan-induced thermal hyperalgesia in both the early phase and the late phase in iNOS knockout mice. We also found that expression of neuronal NOS but not endothelial NOS in the lumbar enlargement segments was significantly increased in iNOS knockout mice compared with wild type mice at 24 h after carrageenan injection. Our results indicate that neuronal NOS might compensate for the function of iNOS in the late phase of carrageenaninduced inflammatory pain in iNOS knockout mice. This suggests that iNOS may be sufficient, but not essential, for the late phase of the carrageenan-induced thermal hyperalgesia. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved.