The peripheral pro-nociceptive state induced by repetitive inflammatory stimuli involves continuous activation of protein kinase A and protein kinase C epsilon and its Na(V)1.8 sodium channel functional regulation in the primary sensory neuron.
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.
Villarreal
Cristiane Flora
CF
Faculty of Pharmacy, Federal University of Bahia, Bahia, Brazil. cfv@ufba.br
Sachs
Daniela
D
Funez
Mani Indiana
MI
Parada
Carlos Amílcar
CA
de Queiroz Cunha
Fernando
F
Ferreira
Sérgio Henrique
SH
D000818:Animals; D001483:Base Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017931:DNA Primers; D015232:Dinoprostone / Q000008:administration & dosage; D004789:Enzyme Activation; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010146:Pain / Q000201:enzymology / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000502:physiology*
D017931:DNA Primers; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568319:Scn10a protein, rat; D015222:Sodium Channels; D017868:Cyclic AMP-Dependent Protein Kinases; D051744:Protein Kinase C-epsilon; D015232:Dinoprostone