Cofilin phosphorylation is involved in nitric oxide/cGMP-mediated nociception.
There is convincing evidence that nitric oxide (NO), cGMP and cGMP-dependent protein kinase I (PKG-I) are involved in the development of hyperalgesia in response to noxious stimuli. However, downstream target proteins contributing to nociception have not been completely identified so far. Several reports indicate a role of the NO/cGMP/PKG cascade in the regulation of neurite outgrowth which is suggested to be involved in specific mechanisms of nociception. Since neurite outgrowth is strongly dependent on modulation of cytoskeleton proteins we were interested in the impact of PKG-I activation on the actin cytoskeleton and its role in inflammatory hyperalgesia. Therefore we investigated the actin-destabilising protein cofilin and its NO-dependent effects in vitro in primary neuronal cultures as well as in vivo in the zymosan-induced paw inflammation model in rats. In primary neurons from rats, treatment with the PKG-I activator 8-Br-cGMP induced a time-dependent phosphorylation of cofilin and significantly increased neurite outgrowth. Further functional analysis revealed that the underlying signal transduction pathways involve activation of the Rho-GTPases RhoA, Rac1 and Cdc42 and their corresponding downstream targets Rho-kinase (ROCK) and p21-activated kinase (PAK). In vivo, treatment of rats with the NO-synthase inhibitor l-NAME and the ROCK-inhibitor Y-27632, respectively, led to a significant decrease of cofilin phosphorylation in the spinal cord and resulted in antinociceptive effects in a model of inflammatory hyperalgesia. Our results suggest that cofilin represents a downstream target of NO/cGMP/PKG signal transduction in neurons thus indicating that it is involved in NO-mediated nociception.
Zulauf
Lars
L
Pharmazentrum frankfurt/ZAFES, Klinikum der Goethe-Universität, Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt, Germany. l.zulauf@hotmail.de
Coste
Ovidiu
O
Marian
Claudiu
C
Möser
Christine
C
Brenneis
Christian
C
Niederberger
Ellen
E
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010147:Pain Measurement; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014226:Triazenes / Q000494:pharmacology; D015054:Zymosan / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C114535:1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene; D051339:Actin Depolymerizing Factors; D020030:Nitric Oxide Donors; D014226:Triazenes; D009569:Nitric Oxide; D015054:Zymosan; D020741:rho GTP-Binding Proteins; D006152:Cyclic GMP