Tegeder Irmgard, Del Turco Domenico, Schmidtko Achim, Sausbier Matthias, Feil Robert, Hofmann Franz, Deller Thomas, Ruth Peter, Geisslinger Gerd
pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany.
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3253-7. doi: 10.1073/pnas.0304076101. Epub 2004 Feb 18.
cGMP-dependent protein kinase I (PKG-I) has been suggested to contribute to the facilitation of nociceptive transmission in the spinal cord presumably by acting as a downstream target of nitric oxide. However, PKG-I activators caused conflicting effects on nociceptive behavior. In the present study we used PKG-I(-/-) mice to further assess the role of PKG-I in nociception. PKG-I deficiency was associated with reduced nociceptive behavior in the formalin assay and zymosan-induced paw inflammation. However, acute thermal nociception in the hot-plate test was unaltered. After spinal delivery of the PKG inhibitor, Rp-8-Br-cGMPS, nociceptive behavior of PKG-I(+/+) mice was indistinguishable from that of PKG-I(-/-) mice. On the other hand, the PKG activator, 8-Br-cGMP (250 nmol intrathecally) caused mechanical allodynia only in PKG-I(+/+) mice, indicating that the presence of PKG-I was essential for this effect. Immunofluorescence studies of the spinal cord revealed additional morphological differences. In the dorsal horn of 3- to 4-week-old PKG-I(-/-) mice laminae I-III were smaller and contained fewer neurons than controls. Furthermore, the density of substance P-positive neurons and fibers was significantly reduced. The paucity of substance P in laminae I-III may contribute to the reduction of nociception in PKG-I(-/-) mice and suggests a role of PKG-I in substance P synthesis.
环磷酸鸟苷依赖性蛋白激酶I（PKG-I）被认为可能通过作为一氧化氮的下游靶点，促进脊髓中的伤害性信息传递。然而，PKG-I激活剂对伤害性行为产生了相互矛盾的影响。在本研究中，我们使用PKG-I基因敲除小鼠进一步评估PKG-I在伤害感受中的作用。在福尔马林试验和酵母聚糖诱导的爪部炎症中，PKG-I缺乏与伤害性行为减少有关。然而，热板试验中的急性热伤害感受未发生改变。脊髓注射PKG抑制剂Rp-8-Br-cGMPS后，PKG-I(+/+)小鼠的伤害性行为与PKG-I(-/-)小鼠无异。另一方面，PKG激活剂8-Br-cGMP（鞘内注射250 nmol）仅在PKG-I(+/+)小鼠中引起机械性异常性疼痛，表明PKG-I的存在对该效应至关重要。脊髓的免疫荧光研究揭示了其他形态学差异。在3至4周龄的PKG-I(-/-)小鼠的背角中，I-III层比对照组小，神经元数量也更少。此外，P物质阳性神经元和纤维的密度显著降低。I-III层中P物质的缺乏可能导致PKG-I(-/-)小鼠伤害感受的降低，并提示PKG-I在P物质合成中发挥作用。
