Dual effects of spinally delivered 8-bromo-cyclic guanosine mono-phosphate (8-bromo-cGMP) in formalin-induced nociception in rats.
The rat formalin assay was used to assess effects of the cyclic guanosine mono-phosphate (cGMP) analog, 8-bromo-cGMP on nociception and cGMP dependent protein kinase I (protein kinase G; PKG-I) expression in lumbar spinal cord. Intrathecal (i.t.) delivery of low doses of 8-bromo-cGMP (0.1-0.25 micromol) reduced nociceptive behavior and formalin-induced upregulation of PKG-I in the spinal cord. Medium doses (0.5-1 micromol i.t.) had no effect and high doses (2.5 micromol i.t.) caused hyperalgesia associated with a further increase of PKG-I expression and a PKG-I clip. To explain these dose-dependent contrary effects we assessed the potential involvement of various cGMP targets: protein kinase G, cyclic nucleotide gated cation channels (CNGs), phosphodiesterases (PDE2 and PDE3) and AMPA-receptors. The PKG inhibitor, Rp-8-bromo-cGMPS did not antagonize the antinociceptive effects of 8-bromo-cGMP but caused antinociception itself. Inhibitors of CNGs, PDE2 and PDE3 had no effect on formalin evoked nociceptive behavior. S-AMPA however, antagonized the antinociceptive effects of 8-bromo-cGMP. Since AMPA receptor currents were found to be reduced by 8-bromo-cGMP in vitro a direct or indirect reduction of AMPA receptor currents might possibly contribute to the antinociceptive effects of 8-bromo-cGMP. On the other hand, 8-bromo-cGMP evoked antinociception appears to be largely independent of PKG-I, CNGs, PDE2 and PDE3. The antinociceptive effects of the PKG inhibitor suggest that a strong PKG activation may be responsible for 'high dose' 8-bromo-cGMP evoked hyperalgesia.
Tegeder
Irmgard
I
Pharmazentrum Frankfurt, Klinikum der Johann Wolfgang Goethe-Universität, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. tegedar@em.uni-frankfurt.de
Schmidtko
Achim
A
Niederberger
Ellen
E
Ruth
Peter
P
Geisslinger
Gerd
G
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000096:biosynthesis; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D005557:Formaldehyde; D006614:Hindlimb; D007278:Injections, Spinal; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000700:Analgesics; D018091:Receptors, AMPA; D005557:Formaldehyde; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D012313:RNA; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517278:Pde2a protein, rat; D006152:Cyclic GMP