Guan Yun, Yaster Myron, Raja Srinivasa N, Tao Yuan-Xiang
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 355 Ross, 720 Rutland Ave,, Baltimore, Maryland 21205, USA.
Mol Pain. 2007 Oct 8;3:29. doi: 10.1186/1744-8069-3-29.
Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 microg/5 microl) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mechanical hypersensitivity on day 7 post-nerve injury in wildtype mice. Intrathecal injection of 7-nitroindazole (8.15 microg/5 microl), a selective nNOS inhibitor, also dramatically attenuated nerve injury-induced mechanical hypersensitivity. Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.
神经元型一氧化氮合酶（nNOS）是神经元组织中产生一氧化氮的关键酶，在炎性疼痛中有助于脊髓中枢敏化。然而，nNOS在神经性疼痛中的作用仍不清楚。本研究结合基因策略和药理学方法，研究nNOS基因敲除和药理学抑制对小鼠单侧第五腰脊神经损伤所致神经性疼痛的影响。与野生型小鼠相比，nNOS基因敲除小鼠未表现出神经损伤诱导的机械性超敏反应。此外，非特异性一氧化氮合酶抑制剂L-NG-硝基-精氨酸甲酯腹腔注射（100 mg/kg）或鞘内注射（30μg/5μl），可显著逆转野生型小鼠神经损伤后第7天神经损伤诱导的机械性超敏反应。鞘内注射选择性nNOS抑制剂7-硝基吲唑（8.15μg/5μl）也可显著减轻神经损伤诱导的机械性超敏反应。蛋白质印迹分析显示，神经损伤后第7天，同侧L5背根神经节中nNOS蛋白表达显著增加，而同侧L5腰脊髓中未增加。神经损伤后，背根神经节或脊髓中诱导型一氧化氮合酶和内皮型一氧化氮合酶蛋白表达未明显改变。我们的研究结果表明，nNOS，尤其是在背根神经节中，可能参与神经损伤后机械性超敏反应的发生和/或维持。
