Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors
Nitric oxide (NO) serves as a retrograde messenger to activate neuronal NO synthase in the spinal cord via NMDA receptors
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DOI：
10.1016/j.niox.2007.04.004
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发表时间：
2007-08-01
影响因子：
3.9
通讯作者：
Ito, Seiji
中科院分区：
文献类型：
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作者：
Xu, Li;Mabuchi, Tamaki;Ito, Seiji
我们最近发现，一氧化氮（NO）产生的神经元NO合酶（nNOS）在脊髓参与维持神经病理性疼痛。为了澄清是否NO本身影响nNOS活性在脊髓作为一个逆行信使，我们研究了参与的NO/cGMP信号通路的nNOS活性的调节NADPH-黄递酶组织化学。NO生成剂NOR 3（t（1/2）= 30 min）和SNAP（t（1/2）= 5 h），而NORI（t（1/2）= 1.8 min），显著增强脊髓中NADPH-黄递酶染色。8-Br-cGMP也增强了它类似于NOR 3，8-Br-cAMP和forskolin，一种腺苷酸环化酶的激活剂，适度地增强了它。NOR 1和NOR 3使脊髓cGMP含量显著增加。NO清除剂CPTIO、可溶性鸟苷酸环化酶抑制剂ODQ和cGMP依赖性蛋白激酶抑制剂KT 5823可显著抑制NOR 3对NADPH-黄递酶染色的增强作用。此外，NOR 3增强的nNOS活性被NMDA拮抗剂MK-801和D-AP 5完全抑制，部分被GluR epsilon 2选择性拮抗剂CP-101，606抑制，并且在GluR epsilon 1（-/-）和GluR epsilon 1（-/-）/epsilon 4（-/-）小鼠中减弱。结果提示，NO可能通过激活含有谷氨酸受体（GluR）1和GluR）2亚基的NMDA受体，作为脊髓内的逆行信使调节nNOS活性。(c)2007爱思唯尔公司All rights reserved.
We have recently demonstrated that nitric oxide (NO) produced by neuronal NO synthase (nNOS) in the spinal cord is involved in the maintenance of neuropathic pain. To clarify whether NO itself affected nNOS activity in the spinal cord as a retrograde messenger, we examined the involvement of the NO/cGMP signaling pathway in the regulation of nNOS activity by NADPH-diaphorase histochemistry. NO-generating agents NOR3 (t(1/2) = 30 min) and SNAP (t(1/2) = 5 h), but not NORI (t(1/2) = 1.8 min), significantly enhanced NADPH-diaphorase staining in the spinal cord. 8-Br-cGMP also enhanced it similar to that by NOR3, and 8-Br-cAMP and forskolin, an activator of adenylate cyclase, enhanced it moderately. NOR I and NOR3 markedly increased the cGMP level in the spinal cord. The enhancement of NADPH-diaphorase staining by NOR3 was significantly inhibited by CPTIO, an NO scavenger, ODQ, a soluble guanylate cyclase inhibitor, and KT5823, an inhibitor of cGMP-dependent protein kinase. Additionally, the NOR3-enhanced nNOS activity was completely inhibited by NMDA antagonists MK-801 and D-AP5, partially by the GluR epsilon 2-selective antagonist CP-101,606, and was attenuated in GluR epsilon 1(-/-) and GluR epsilon 1(-/-)/epsilon 4(-/-) mice. These results suggest that NO may regulate nNOS activity as a retrograde messenger in the spinal cord via activation of NMDA receptor containing GluR epsilon 1 and GluR epsilon 2 subunits. (c) 2007 Elsevier Inc. All rights reserved.