Lin Q, Wu J, Peng Y B, Cui M, Willis W D
Department of Anatomy and Neurosciences, Marine Biomedical Institute, The University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
J Neurophysiol. 1999 Mar;81(3):1095-103. doi: 10.1152/jn.1999.81.3.1095.
Our recent work has suggested that the nitric oxide/guanosine 3', 5'-cyclic monophosphate (NO/cGMP) signal transduction system contributes to central sensitization of spinothalamic tract (STT) neurons in part by influencing the descending inhibition of nociception resulting from stimulation in the periaqueductal gray. This study was designed to examine further whether activation of the NO/cGMP cascade reduces the inhibition of the activity of STT neurons mediated by spinal inhibitory amino acid (IAA) receptors. Responses of STT cells to noxious cutaneous stimuli were inhibited by iontophoresis of glycine and GABA agonists in anesthetized monkeys. Administration of 8-bromoguanosine-3',5'-cyclophosphate sodium (8-bromo-cGMP), a membrane permeable analogue of cGMP, either by microdialysis or by iontophoresis reduced significantly the IAA-induced inhibition of wide dynamic range (WDR) STT cells in the deep layers of the dorsal horn. The reduction in inhibition lasted for up to 1-1.5 h after the cessation of drug infusion. In contrast, IAA-induced inhibition of WDR STT cells in the superficial dorsal horn and high-threshold (HT) cells in superficial or deep layers was not significantly changed during 8-bromo-cGMP infusion. Iontophoresis of 8-bromo-cGMP onto STT cells produced the same actions as produced by microdialysis of this agent, but the effect was not as long-lasting nor as potent. Finally, an attenuation of the IAA receptor-mediated inhibition of STT cells produced by iontophoretic release of a NO donor, 3-morpholinosydnonimine, could be blocked by pretreatment of the spinal cord with a guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. These results suggest that an increased spinal cGMP level contributes to the sensitization of WDR STT neurons in the deep dorsal horn in part by down-regulating spinal IAA receptors. However, no evidence is provided in this study that the NO/cGMP cascade regulates IAA receptors on HT and superficial WDR neurons. Combined with the preceding studies, our data support the view that NO and cGMP function in the same signal transduction cascade and play an important role in central sensitization.
我们最近的研究表明，一氧化氮/鸟苷3',5'-环磷酸（NO/cGMP）信号转导系统部分地通过影响导水管周围灰质刺激所产生的伤害性感受下行抑制，对脊髓丘脑束（STT）神经元的中枢敏化起作用。本研究旨在进一步检测NO/cGMP级联的激活是否会降低由脊髓抑制性氨基酸（IAA）受体介导的STT神经元活动的抑制。在麻醉的猴子中，甘氨酸和GABA激动剂的离子导入抑制了STT细胞对有害皮肤刺激的反应。通过微透析或离子导入给予8-溴鸟苷-3',5'-环磷酸钠（8-溴-cGMP），一种cGMP的膜通透性类似物，显著降低了IAA诱导的背角深层广动力范围（WDR）STT细胞的抑制。在停止药物输注后，抑制作用的降低持续长达1 - 1.5小时。相反，在8-溴-cGMP输注期间，IAA诱导的背角浅层WDR STT细胞以及浅层或深层高阈值（HT）细胞的抑制没有显著变化。将8-溴-cGMP离子导入STT细胞产生的作用与该药物微透析产生的作用相同，但效果没有那么持久和强大。最后，离子导入释放NO供体3-吗啉代非对称二亚胺所产生的IAA受体介导的STT细胞抑制作用的减弱，可被用鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮预处理脊髓所阻断。这些结果表明，脊髓cGMP水平的升高部分地通过下调脊髓IAA受体，导致背角深层WDR STT神经元的敏化。然而，本研究没有提供证据表明NO/cGMP级联调节HT和浅层WDR神经元上的IAA受体。结合先前的研究，我们的数据支持NO和cGMP在同一信号转导级联中发挥作用并在中枢敏化中起重要作用的观点。
