Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production
Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production
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DOI：
10.1046/j.1460-9568.2003.02575.x
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发表时间：
2003-04-01
影响因子：
3.4
通讯作者：
Ito, S
中科院分区：
文献类型：
--
作者：
Mabuchi, T;Matsumura, S;Ito, S
在脊髓水平，伤害素/孤儿蛋白FQ(N/OFQ)在疼痛传递中的作用是有争议的。JTC-801是一种选择性的非肽能N/OFQ拮抗剂，是研究内源性N/OFQ参与病理生理过程的良好工具。在本研究中，我们研究了JTC-801对小鼠L5脊神经切断所致神经病理性疼痛的影响。术后第3天出现明显的热痛觉过敏，并持续至10天实验期。口服JTC-801可剂量依赖性地减轻神经性小鼠的热痛敏反应。L5神经切断后，NADPH黄递酶组织化学显示脊髓背角浅层及中央管周围一氧化氮合酶(NOS)活性增强。应用新型一氧化氮(NO)荧光染料二氨基荧光素-FM，我们证实了神经病小鼠脊髓切片中NO的产生增加，并且在神经切断的同侧比对侧更显著。口服JTC-801可阻断神经病小鼠一氧化氮合酶活性和一氧化氮生成的增加。虽然腹腔注射非选择性一氧化氮合酶抑制剂N(G.)-硝基-L-精氨酸甲酯，但显著减轻神经病理性痛觉过敏，诱导型一氧化氮合酶缺陷小鼠L5脊神经切断后出现神经病理性疼痛。上述结果提示，N/OFQ参与了神经病理性疼痛的维持，JTC-801对神经病理性疼痛的镇痛作用是通过抑制神经元型一氧化氮合酶产生NO来实现的。
At the spinal level, the involvement of nociceptin/orphanin FQ (N/OFQ) in pain transmission is controversial. JTC-801, a selective nonpeptidergic N/OFQ antagonist, is a good tool to examine the involvement of endogenous N/OFQ in pathophysiological conditions. In the present study, we studied the effect of JTC-801 on neuropathic pain induced by L5 spinal nerve transection in mice. Thermal hyperalgesia was evident on day 3 postsurgery and maintained during the 10-day experimental period. Oral administration of JTC-801 relieved the thermal hyperalgesia in neuropathic mice in a dose-dependent manner. Following L5 nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn and around the central canal in the spinal cord by NADPH diaphorase histochemistry. Using the novel fluorescent nitric oxide (NO) detection dye diaminofluorescein-FM, we confirmed that NO production increased in the spinal slice prepared from neuropathic mice and that the increase was more prominent in the ipsilateral side to the nerve transection than in the contralateral side. These increases in NOS activity and NO production in neuropathic mice were blocked by pretreatment of oral JTC-801. Although intraperitoneal injection of the nonselective NOS inhibitor N (G.) -nitro-L-arginine methyl ester transiently, but significantly, attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transection. These results suggest that N/OFQ is involved in the maintenance of neuropathic pain and that the analgesic effect of JTC-801 on neuropathic pain is mediated by inhibition of NO production by neuronal NOS.