Villarreal Cristiane Flora, Sachs Daniela, Funez Mani Indiana, Parada Carlos Amílcar, de Queiroz Cunha Fernando, Ferreira Sérgio Henrique
Faculty of Pharmacy, Federal University of Bahia, Bahia, Brazil.
Biochem Pharmacol. 2009 Mar 1;77(5):867-77. doi: 10.1016/j.bcp.2008.11.015. Epub 2008 Nov 25.
In the present study, the participation of the Na(V)1.8 sodium channel was investigated in the development of the peripheral pro-nociceptive state induced by daily intraplantar injections of PGE(2) in rats and its regulation in vivo by protein kinase A (PKA) and protein kinase C epsilon (PKCvarepsilon) as well. In the prostaglandin E(2) (PGE(2))-induced persistent hypernociception, the Na(V)1.8 mRNA in the dorsal root ganglia (DRG) was up-regulated. The local treatment with dipyrone abolished this persistent hypernociception but did not alter the Na(V)1.8 mRNA level in the DRG. Daily intrathecal administrations of antisense Na(V)1.8 decreased the Na(V)1.8 mRNA in the DRG and reduced ongoing persistent hypernociception. Once the persistent hypernociception had been abolished by dipyrone, but not by Na(V)1.8 antisense treatment, a small dose of PGE(2) restored the hypernociceptive plateau. These data show that, after a period of recurring inflammatory stimuli, an intense and prolonged nociceptive response is elicited by a minimum inflammatory stimulus and that this pro-nociceptive state depends on Na(V)1.8 mRNA up-regulation in the DRG. In addition, during the persistent hypernociceptive state, the PKA and PKCvarepsilon expression and activity in the DRG are up-regulated and the administration of the PKA and PKCvarepsilon inhibitors reduce the hypernociception as well as the Na(V)1.8 mRNA level. In the present study, we demonstrated that the functional regulation of the Na(V)1.8 mRNA by PKA and PKCvarepsilon in the primary sensory neuron is important for the development of the peripheral pro-nociceptive state induced by repetitive inflammatory stimuli and for the maintenance of the behavioral persistent hypernociception.
在本研究中，研究了Na(V)1.8钠通道在大鼠足底每日注射前列腺素E2（PGE2）诱导的外周伤害性感受状态发展中的作用，以及蛋白激酶A（PKA）和蛋白激酶Cε（PKCε）在体内对其的调节作用。在前列腺素E2（PGE2）诱导的持续性痛觉过敏中，背根神经节（DRG）中的Na(V)1.8 mRNA上调。用安乃近局部治疗可消除这种持续性痛觉过敏，但不会改变DRG中Na(V)1.8 mRNA水平。每日鞘内注射反义Na(V)1.8可降低DRG中Na(V)1.8 mRNA水平，并减轻持续的持续性痛觉过敏。一旦安乃近消除了持续性痛觉过敏，但反义Na(V)1.8治疗未消除，小剂量的PGE2可恢复痛觉过敏平台期。这些数据表明，在一段反复的炎症刺激后，最小的炎症刺激可引发强烈且持久的伤害性反应，并且这种伤害性感受状态取决于DRG中Na(V)1.8 mRNA的上调。此外，在持续性痛觉过敏状态下，DRG中PKA和PKCε的表达及活性上调，PKA和PKCε抑制剂的给药也可减轻痛觉过敏以及Na(V)1.8 mRNA水平。在本研究中，我们证明了PKA和PKCε对初级感觉神经元中Na(V)1.8 mRNA的功能调节对于重复性炎症刺激诱导的外周伤害性感受状态的发展以及行为性持续性痛觉过敏的维持至关重要。
