Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury
Transient action of the endothelial constitutive nitric oxide synthase (ecNOS) mediates the development of thermal hypersensitivity following peripheral nerve injury
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DOI：
10.1046/j.1460-9568.2000.00129.x
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发表时间：
2000-07-01
影响因子：
3.4
通讯作者：
Zochodne, DW
中科院分区：
文献类型：
--
作者：
Levy, D;Tal, M;Zochodne, DW
神经性疼痛是周围神经损伤的一个致残特征。损伤后，局部炎症和介质释放可能导致神经干的异位机械敏感性和疼痛过敏。在本研究中，我们研究了一氧化氮 (NO) 作用和局部一氧化氮合酶 (NOS) 表达是否在大鼠坐骨神经慢性收缩损伤后的疼痛超敏性和 A 纤维介导的异位过度兴奋中发挥作用。使用免疫组织化学方法，我们为受损周围神经轴突的早期轴突终球样结构中独特的内皮组成型一氧化氮合酶（ecNOS）免疫反应性提供了证据。此外，我们发现，神经损伤后，腰交感神经节内 ecNOS-mRNA 表达增加，并且交感神经和其他轴突中的轴浆运输而不是局部非神经合成解释了其在神经纤维中的积累。我们还在此证明，用广谱抑制剂 N-G-硝基-L-精氨酸甲酯 (L-NAME) 局部抑制 NOS 作用，而不是其他 NOS 亚型的更特异性抑制剂，具有立体特异性、剂量和时间依赖性的镇痛作用，局部给予 L-精氨酸（NO 的天然前体）可逆转这种作用。在进一步的工作中，使用经过梳理的纤维制剂，我们表明，在损伤部位施用 l-NAME（而不是 d-NAME）也可以阻止受伤 A 纤维的异位机械敏感性。我们的结果表明，早期轴突终球样结构中早期和短暂的局部 ecNOS 表达（其中一些源自交感神经轴突）在神经性疼痛的发展中发挥着关键作用。
Neuropathic pain is a disabling feature of peripheral nerve injury. Following injury, local inflammation and the release of mediators may contribute to ectopic mechanosensitivity of the nerve-trunk and pain hypersensitivity. In the present study we investigated whether nitric oxide (NO) action and local nitric oxide synthase (NOS) expression play a role in pain hypersensitivity and A fibre-mediated ectopic hyperexcitability following a chronic constriction injury to a rat sciatic nerve. Using immunohistochemical methods we provide evidence for a unique endothelial constitutive nitric oxide synthase (ecNOS) immunoreactivity localized in early axonal endbulb-like structures of injured peripheral nerve axons. Moreover, we show that following nerve injury there is increased ecNOS-mRNA expression within the lumbar sympathetic ganglia, and that axoplasmic transport in sympathetic and other axons rather than local non-neural synthesis accounts for its accumulation in nerve fibres. We also demonstrate here that local inhibition of NOS action with the broad-spectrum inhibitor N-G-nitro-l-arginine-methyl ester (l-NAME), but not more specific inhibitors of other NOS isoforms, has stereospecific, dose- and time-dependent analgesic effects that were reversed by local administration of l-arginine, the natural precursor of NO. In further work, using a teased fibre preparation, we show that administration of l-NAME, but not d-NAME, to the injury site also blocks ectopic mechanosensitivity of injured A-fibres. Our results indicate that an early and transient local ecNOS expression within early axonal endbulb-like structures, some arising from sympathetic axons, plays a critical role in the development of neuropathic pain.