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.