Reduced inflammatory hyperalgesia with preservation of acute thermal nociception in mice lacking cGMP-dependent protein kinase I.

Abstract

cGMP-dependent protein kinase I (PKG-I) has been suggested to contribute to the facilitation of nociceptive transmission in the spinal cord presumably by acting as a downstream target of nitric oxide. However, PKG-I activators caused conflicting effects on nociceptive behavior. In the present study we used PKG-I(-/-) mice to further assess the role of PKG-I in nociception. PKG-I deficiency was associated with reduced nociceptive behavior in the formalin assay and zymosan-induced paw inflammation. However, acute thermal nociception in the hot-plate test was unaltered. After spinal delivery of the PKG inhibitor, Rp-8-Br-cGMPS, nociceptive behavior of PKG-I(+/+) mice was indistinguishable from that of PKG-I(-/-) mice. On the other hand, the PKG activator, 8-Br-cGMP (250 nmol intrathecally) caused mechanical allodynia only in PKG-I(+/+) mice, indicating that the presence of PKG-I was essential for this effect. Immunofluorescence studies of the spinal cord revealed additional morphological differences. In the dorsal horn of 3- to 4-week-old PKG-I(-/-) mice laminae I-III were smaller and contained fewer neurons than controls. Furthermore, the density of substance P-positive neurons and fibers was significantly reduced. The paucity of substance P in laminae I-III may contribute to the reduction of nociception in PKG-I(-/-) mice and suggests a role of PKG-I in substance P synthesis.

• Authors: Irmgard Tegeder, Domenico Del Turco, Achim Schmidtko, Matthias Sausbier, Robert Feil, Franz Hofmann, Thomas Deller, Peter Ruth, Gerd Geisslinger
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 101 Issue 9 Pg. 3253-7 (Mar 02 2004) ISSN: 0027-8424 [Print] United States
• PMID: 14973199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thionucleotides
• 8-bromoguanosino-3',5'-cyclic monophosphorothioate
• Formaldehyde
• Substance P
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP

Topics

• Animals
• Cyclic GMP (analogs & derivatives, pharmacology)
• Cyclic GMP-Dependent Protein Kinases (antagonists & inhibitors, deficiency, genetics)
• Disease Models, Animal
• Formaldehyde
• Hot Temperature
• Hyperalgesia (genetics, prevention & control)
• Inflammation (genetics, prevention & control)
• Mice
• Mice, Knockout
• Neurons (physiology)
• Pain (chemically induced, genetics, physiopathology)
• Reaction Time
• Substance P (physiology)
• Thionucleotides (pharmacology)