Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain
Effect of genetic knockout or pharmacologic inhibition of neuronal nitric oxide synthase on complete Freund's adjuvant-induced persistent pain
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DOI：
10.1016/j.pain.2005.09.024
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发表时间：
2005-12-15
期刊：
影响因子：
7.4
通讯作者：
Tao, YX
中科院分区：
文献类型：
--
作者：
Chu, YC;Guan, Y;Tao, YX
一氧化氮(NO)是一种神经递质或神经调节剂，参与热性和/或炎症性痛觉过敏的调节。神经元型一氧化氮合酶(NNOS)是正常神经组织中产生NO的关键酶，但其在慢性疼痛中的作用尚不清楚。本研究结合遗传策略和药理学方法，探讨nNOS在完全弗氏佐剂(CFA)诱导慢性炎症性疼痛的中枢机制中的作用。在炎性疼痛的维持(但不是发展)过程中，靶向阻断nNOS基因显著降低了CFA诱导的机械性疼痛超敏反应，但它不能减弱CFA诱导的热痛超敏反应的发展或维持。L-N-G-硝基-精氨酸甲酯(L-NAME)是一种非特异性一氧化氮合酶抑制剂，在发育期(2 H)和维持期(24 H)均可阻断CFA诱导的小鼠热痛觉和机械性痛过敏反应，但对基因敲除小鼠无明显影响。此外，鞘内注射选择性一氧化氮合酶抑制剂L或7-硝基吲唑均可明显减轻注射CFA后2、24天的机械痛过敏反应。注射CFA后24 h，脊髓nNOS(而不是内皮型或诱导型)表达上调，主要出现在同侧背角浅层。综上所述，这些数据表明，脊髓nNOS可能是维持机械痛超敏所必需的，也可能对机械痛超敏的发展和慢性炎症后热痛超敏的形成和维持是足够的。我们的研究结果表明，脊髓nNOS可能在慢性炎症性疼痛的发生和/或维持的中枢机制中发挥关键作用。(C)2005年国际疼痛研究协会。爱思唯尔出版，版权所有。
Nitric oxide (NO) acts as a neurotransmitter or neuromodulator involving in the modulation of thermal and/or inflammatory hyperalgesia. The neuronal nitric oxide synthase (nNOS) is a key enzyme for NO production in normal neuronal tissues, but its functional role in chronic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to address the role of nNOS in the central mechanism of complete Freund's adjuvant (CFA)-induced chronic inflammatory pain. Targeted disruption of the nNOS gene significantly reduced CFA-induced mechanical pain hypersensitivity during the maintenance (but not the development) of inflammatory pain, while it failed to attenuate either development or maintenance of CFA-induced thermal pain hypersensitivity. Intraperitoneal administration of L-N-G-nitro-arginine methyl ester (L-NAME), a non-specific NOS inhibitor, blocked CFA-evoked thermal and mechanical pain hypersensitivity at both development (2 h) and maintenance (24 h) phase in wild type mice, but had no effect in the knockout mice. Furthermore, intrathecal injection of either L-NAME or 7-nitroindazole, a selective nNOS inhibitor, markedly attenuated mechanical pain hypersensitivity at both 2 and 24 It after CFA injection. Finally, spinal cord nNOS (but not endothelial NOS or inducible NOS) expression was up-regulated at 24 h after CFA injection, occurring mainly in the ipsilateral superficial dorsal horn. Together, these data indicate that spinal cord nNOS may be essential for the maintenance of mechanical pain hypersensitivity and that it may also be sufficient for the development of mechanical pain hypersensitivity and for the development and maintenance of thermal pain hypersensitivity after chronic inflammation. Our findings suggest that spinal cord nNOS might play a critical role in central mechanisms of the development and/or maintenance of chronic inflammatory pain. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.