Inhibition of cyclic guanosine 5'-monophosphate-dependent protein kinase I (PKG-I) in lumbar spinal cord reduces formalin-induced hyperalgesia and PKG upregulation.
Nitric oxide-mediated nociception has been suggested to involve formation of cyclic guanosine 5'-monophosphate (cGMP) and activation of cGMP-dependent protein kinase (PKG). To further evaluate this pathway we assessed the effects of the PKG-inhibiting cGMP analog Rp-8-Br-cGMPS in the rat formalin assay and analyzed the regulation of PKG expression in rat lumbar spinal cord. Spinally delivered Rp-8-Br-cGMPS (0.1-0.5 micro mol i.t.) reduced the nociceptive behavior in a dose-dependent manner. Similar effects were achieved with Rp-8-Br-PET-cGMPS (0.5 micro mol i.t.), another PKG-inhibitory cGMP analog. In contrast, Rp-8-Br-cAMPS (0.5 micro mol i.t.), an inhibitor of protein kinase A, had no effect in this model. Formalin treatment resulted in a rapid (within 1h), long-lasting (up to 96h) upregulation of PKG-I protein expression. This increase was prevented in animals pretreated with Rp-8-Br-cGMPS (0.5 micro mol i.t.) or morphine (2.5-5mg/kg i.p.) 10min prior to formalin injection. Spinal delivery of 8-Br-cGMP, a PKG-activating cGMP analog, without subsequent formalin treatment also caused an increase of PKG-I protein expression. Hence, the upregulation of PKG-I might possibly be mediated by cGMP itself. Our data suggest that PKG-I activation is involved in the synaptic transmission of nociceptive stimuli in the spinal cord and that PKG-I inhibitors might be interesting novel drugs for pain treatment.
Schmidtko
Achim
A
pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, Frankfurt am Main, 60590, Germany.
Ruth
Peter
P
Geisslinger
Gerd
G
Tegeder
Irmgard
I
D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D008159:Lumbar Vertebrae; D009569:Nitric Oxide / Q000633:toxicity; D010147:Pain Measurement; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D013873:Thionucleotides; C083763:8-bromoguanosino-3',5'-cyclic monophosphorothioate; C098740:8-bromo-beta-phenyl-1,N(2)-ethenoguanosine 3',5'-cyclic monophosphorothioate; D005557:Formaldehyde; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP