The p21-activated kinase PAK 5 is involved in formalin-induced nociception through regulation of MAP-kinase signaling and formalin-specific receptors.
p21-activated kinases (PAKs) are involved in signal cascades relevant for nociceptive processing and neuropathic pain. Particularly, the recently described group B PAKs 4, 5 and 6 regulate MAP-kinases and the rearrangement of the actin cytoskeleton, both of which have been linked to pain processing. However, a specific role of these PAKs in nociception has not yet been demonstrated. We found PAK 4, 5 and 6 expression in pain-relevant tissues in peripheral and CNS. Since viable knock-out mice only exist for the PAK isoform 5, we further assessed the impact of this PAK on acute and chronic pain using different behavioral models in mice. PAK 5 knock-out mice showed normal acute nociception and did not differ from wild type mice in their neuropathic pain behavior. However, the nociceptive response in formalin-induced paw inflammation was significantly reduced in knock-out mice associated with inhibition of MAP-kinase activation and a decreased number of formalin-induced c-Fos positive neurons in the spinal cord. Furthermore, in isolated neurons, we found a significantly reduced calcium response after stimulation of TRPA1-channels in PAK 5(-/-)- compared to PAK 5(+/+)-cells. Our results indicate that PAK 5 is involved in formalin-induced inflammatory nociception through regulation of MAPK-induced c-Fos-activation and formalin-specific TRP-channels.
Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt, Theodor Stern Kai 7, 60590 Frankfurt am Main, Germany. ovidiu_coste@yahoo.com
Ovidiu
O
Coste
Christine V
CV
Möser
Marco
M
Sisignano
Katharina L
KL
Kynast
Audrey
A
Minden
Gerd
G
Geisslinger
Ellen
E
Niederberger
D000818:Animals; D005557:Formaldehyde / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced*; D059225:Nociception / Q000502:physiology; D010147:Pain Measurement / Q000379:methods; D054462:p21-Activated Kinases / Q000378:metabolism*
D005557:Formaldehyde; C486708:Pak7 protein, mouse; D054462:p21-Activated Kinases; D020928:Mitogen-Activated Protein Kinases