Spatio-temporal analysis by optical imaging of neural plasticity mechanism in neuropathic pain.

周围神经损伤引起的神经病理性疼痛常表现为顽固性疼痛，并伴有触觉痛（触诱发痛）和痛觉过敏，本实验采用L5脊神经切断致小鼠神经病理性疼痛后，用NADPH黄递酶组织化学方法观察到脊髓背角浅层一氧化氮合酶（NOS）活性增高。使用一氧化氮（NO）检测染料，我们证实，NO的生产增加，在脊髓切片从神经病小鼠和增加更突出的同侧的神经横断比对侧。这些增加的NOS活性和NO的产生在神经病小鼠被阻断的口服JTC-801，非肽能nociceptin拮抗剂预处理。尽管腹腔注射非选择性NOS抑制剂显著减弱了神经性痛觉过敏，但诱导型NOS缺陷小鼠在L5脊神经切断后表现出神经性疼痛。 ...更多信息 n.这些结果表明，伤害感受素参与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NOS产生NO来介导的。缺乏PACAP基因（PACAP^<-/->）的小鼠没有表现出神经切断诱导的神经病理性疼痛，然而它们确实保留了正常的伤害感受反应。鞘内注射NMDA在野生型小鼠中诱导了机械性异常性疼痛，但在PACAP-/-小鼠中没有。通过同时鞘内注射PACAP和NMDA，在PACAP-/-小鼠中复制NMDA诱导的异常性疼痛。伴随着神经损伤后PACAP免疫反应性的增加，野生型小鼠脊髓浅层的NADPH依赖性NOS活性显著增加。同时加入PACAP和NMDA引起易位的神经元NOS从胞质到膜和刺激NO的产生在体外。这些结果表明，PACAP可能促进神经元NOS与NMDA受体的功能性偶联，从而导致神经病理性疼痛的发生。少

Neuropathic pain arising from peripheral nerve injury often becomes intractable pain accompanied by tactile pain (allodynia) and hyperalgesia.After mice had become neuropathic pain induced by L5 spinal nerve transection, the increase in nitric oxide synthase (NOS) activity was observed in the superficial layer of dorsal horn in the spinal cord by NADPH diaphorase histochemistry. Using the nitric oxide (NO) detection dye, 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, non peptidergic nociceptin antagonist. Although intraperitoneal injection of the nonselective NOS inhibitor significantly attenuated neuropathic hyperalgesia, inducible NOS-deficient mice showed neuropathic pain after L5 spinal nerve transectio … More n. These results suggest that nociceptin 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.Mice lacking the PACAP gene (PACAP^<-/->) did not exhibit neuropathic pain induced by nerve transection, whereas they did retain normal nociceptive responses. Intrathecal administration of NMDA induced mechanical allodynia in wild-type mice, but not in PACAP-/- mice. The NMDA-induced allodynia in PACAP-/- mice was reproduced by simultaneous intrathecal injection of PACAP with NMDA. Concomitant with the increase in PACAP immunoreactivity after nerve injury, NADPH-dependent NOS activity markedly increased in the superficial layer of the spinal cord of wild-type mice. Simultaneous addition of PACAP and NMDA caused translocation of neuronal NOS from the cytosol to the membrane and stimulated NO production in vitro. These results demonstrate that PACAP might promote the functional coupling of neuronal NOS to NMDA receptors for neuropathic pain to occur. Less