Tao Y X, Hassan A, Haddad E, Johns R A
Department of Anesthesia and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287-4965, USA.
Neuroscience. 2000;95(2):525-33. doi: 10.1016/s0306-4522(99)00438-8.
Several lines of evidence have shown a role for the nitric oxide/cyclic guanosine monophosphate signaling pathway in the development of spinal hyperalgesia. However, the roles of effectors for cyclic guanosine monophosphate are not fully understood in the processing of pain in the spinal cord. The present study showed that cyclic guanosine monophosphate-dependent protein kinase Ialpha but not Ibeta was localized in the neuronal bodies and processes, and was distributed primarily in the superficial laminae of the spinal cord. Intrathecal administration of a selective inhibitor of cyclic guanosine monophosphate-dependent protein kinase Ialpha, Rp-8-[(4-chlorophenyl)thio]-cGMPS triethylamine, produced a significant antinociception demonstrated by the decrease in the number of flinches and shakes in the formalin test. This was accompanied by a marked reduction in formalin-induced c-fos expression in the spinal dorsal horn. Moreover, cyclic guanosine monophosphate-dependent protein kinase Ialpha protein expression was dramatically increased in the lumbar spinal cord 96 h after injection of formalin into a hindpaw, which occurred mainly in the superficial laminae on the ipsilateral side of a formalin-injected hindpaw. This up-regulation of cyclic guanosine monophosphate-dependent protein kinase Ialpha expression was completely blocked not only by a neuronal nitric oxide synthase inhibitor, 7-nitroindazole, and a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, but also by an N-methyl-D-aspartate receptor antagonist, dizocilpine maleate (MK-801). The present results indicate that noxious stimulation not only initially activates but also later up-regulates cyclic guanosine monophosphate-dependent protein kinase Ialpha expression in the superficial laminae via an N-methyl-D-aspartate-nitric oxide-cyclic guanosine monophosphate signaling pathway, suggesting that cyclic guanosine monophosphate-dependent protein kinase Ialpha may play an important role in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
多条证据表明一氧化氮/环磷酸鸟苷信号通路在脊髓痛觉过敏的发生中起作用。然而，环磷酸鸟苷效应器在脊髓疼痛处理中的作用尚未完全明确。本研究表明，环磷酸鸟苷依赖性蛋白激酶Iα而非Iβ定位于神经元胞体和突起中，且主要分布于脊髓浅层。鞘内注射环磷酸鸟苷依赖性蛋白激酶Iα的选择性抑制剂Rp-8-[(4-氯苯基)硫代]-cGMPS三乙胺，在福尔马林试验中可通过减少退缩和抖动次数显示出显著的抗伤害感受作用。这伴随着福尔马林诱导的脊髓背角c-fos表达的显著降低。此外，在后爪注射福尔马林96小时后，腰段脊髓中环磷酸鸟苷依赖性蛋白激酶Iα的蛋白表达显著增加，主要发生在注射福尔马林后爪同侧的浅层。环磷酸鸟苷依赖性蛋白激酶Iα表达的这种上调不仅被神经元型一氧化氮合酶抑制剂7-硝基吲唑和可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮完全阻断，也被N-甲基-D-天冬氨酸受体拮抗剂马来酸氯胺酮（MK-801）完全阻断。本研究结果表明，伤害性刺激不仅最初激活，而且随后通过N-甲基-D-天冬氨酸-一氧化氮-环磷酸鸟苷信号通路上调脊髓浅层中环磷酸鸟苷依赖性蛋白激酶Iα的表达，提示环磷酸鸟苷依赖性蛋白激酶Iα可能在脊髓福尔马林诱导的炎性痛觉过敏的中枢机制中起重要作用。
