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Volume 5 Supplement 1

2nd International Conference of cGMP Generators, Effectors and Therapeutic Implications

The role of cGMP and PKG-I in spinal nociceptive processing

BMC Pharmacology volume 5, Article number: P50 (2005) Cite this article

Background

Persistent stimulation of nociceptors results in sensitization of nociceptive sensory neurons, which is associated with hyperalgesia and allodynia. The release of NO and subsequent synthesis of cGMP in the spinal cord are involved in this process. cGMP-dependent protein kinase I (PKG-I) has been suggested to act as a downstream target of cGMP, but its exact role in nociception hadn't been characterized yet. To further evaluate the NO/cGMP/PKG-I pathway in nociception we assessed the effects of PKG-I inhibiton and activaton in the rat formalin assay and analyzed the nociceptive behavior of PKG-I-/- mice.

Results

The PKG-I-inhibitor, Rp-8-Br-cGMPS (0.1 – 0.5 μmol i.t.), reduced the nociceptive behaviour of rats in the formalin assay [1]. In contrast, administration of a high dose (2.5 μmol i.t.) of the cGMP analogue, 8-Br-cGMP, caused hyperalgesia. However, low doses of the same drug (0.1 – 0.25 μmol i.t.) unexpectedly reduced the nociceptive behaviour, revealing dose-dependent contrary effects of 8-Br-cGMP. The antinociceptive effects of 'low-dose' 8-Br-cGMP are obviously independent of PKG-I activation, since co-administration with the PKG-I inhibitor, Rp-8-Br-cGMPS, failed to antagonize antinociception [2]. To further assess the role of PKG-I in nociception, we studied the behaviour of PKG-I-/- mice. PKG-I deficiency was associated with reduced nociceptive behaviour in the formalin assay and reduced mechanical hyperalgesia during zymosan-induced paw inflammation. A high dose of 8-Br-cGMP (250 nmol i.t.) caused mechanical allodynia only in PKG-I+/+ mice, indicating that the presence of PKG-I was essential for this pronociceptive effect. In contrast, administration of 'low-dose' 8-Br-cGMP (25 nmol i.t.) reduced the nociceptive behaviour in both PKG-I+/+ and PKG-I-/- mice, supporting the hypothesis that the antinociceptive effects of 8-Br-cGMP are independent of PKG-I activation [3].

Conclusions

Our data suggest that in the spinal cord, high concentrations of cGMP cause hyperalgesia through activation of PKG-I, whereas low concentrations of cGMP reveal antinociceptive effects via a PKG-I-independent mechanism.

References

  1. Schmidtko A, Ruth P, Geisslinger G, Tegeder I: 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. 2003, 8: 89-94. 10.1016/S1089-8603(02)00165-9.

    Article  CAS  PubMed  Google Scholar 

  2. Tegeder I, Schmidtko A, Niederberger E, Ruth P, Geisslinger G: Dual effects of spinally delivered 8-bromo-cyclic guanosine mono-phosphate (8-bromo-cGMP) in formalin-induced nociception in rats. Neurosci Lett. 2002, 332: 146-150. 10.1016/S0304-3940(02)00938-2.

    Article  CAS  PubMed  Google Scholar 

  3. Tegeder I, Del Turco D, Schmidtko A, Sausbier M, Feil R, Hofmann F, Deller T, Ruth P, Geisslinger G: Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase-I. Proc Natl Acad Sci U S A. 2004, 101: 3253-3257. 10.1073/pnas.0304076101.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

Our studies were supported by the Deutsche Forschungsgemeinschaft [SFB 553 (C6)].

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Authors and Affiliations

  1. Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

    Achim Schmidtko, Irmgard Tegeder, Ellen Niederberger & Gerd Geisslinger

  2. Institut für Pharmakologie und Toxikologie, Technische Universität München, Germany

    Franz Hofmann

  3. Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universität Tübingen, Germany

    Peter Ruth

Authors
  1. Achim Schmidtko
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  2. Irmgard Tegeder
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  3. Ellen Niederberger
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  4. Franz Hofmann
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  5. Peter Ruth
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  6. Gerd Geisslinger
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Corresponding author

Correspondence to Achim Schmidtko.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Schmidtko, A., Tegeder, I., Niederberger, E. et al. The role of cGMP and PKG-I in spinal nociceptive processing. BMC Pharmacol 5 (Suppl 1), P50 (2005). https://doi.org/10.1186/1471-2210-5-S1-P50

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  • DOI: https://doi.org/10.1186/1471-2210-5-S1-P50

Keywords

  • Spinal Cord
  • Protein Kinase
  • Sensory Neuron
  • Downstream Target
  • Exact Role

BMC Pharmacology

ISSN: 1471-2210