Oxidant-induced activation of cGMP-dependent protein kinase Iα mediates neuropathic pain after peripheral nerve injury.
OBJECTIVE
Emerging lines of evidence indicate that oxidants such as hydrogen peroxide exert specific signaling functions during the processing of chronic pain. However, the mechanisms by which oxidants regulate pain processing in vivo remain poorly understood. Here, we investigated whether cyclic guanosine monophosphate (cGMP)-dependent protein kinase Iα (cGKIα), which can be activated by oxidants independently of cGMP, serves as a primary redox target during pain processing.


RESULTS
After peripheral nerve injury, oxidant-induced cGKIα activation is increased in dorsal root ganglia of mice. Knock-in (KI) mice in which cGKIα cannot transduce oxidant signals demonstrated reduced neuropathic pain behaviors after peripheral nerve injury, and reduced pain behaviors after intrathecal delivery of oxidants. In contrast, acute nociceptive, inflammatory, and cGMP-induced pain behaviors were not impaired in these mice.


METHODS
Studying cGKIα KI mice, we provide the first evidence that oxidants activate cGKIα in sensory neurons after peripheral nerve injury in vivo.


CONCLUSIONS
Our results suggest that oxidant-induced activation of cGKIα specifically contributes to neuropathic pain processing, and that prevention of cGKIα redox activation could be a potential novel strategy to manage neuropathic pain.
1 Pharmazentrum Frankfurt/ZAFES, Institut für Klinische Pharmakologie, Universitätsklinikum Frankfurt , Frankfurt am Main, Germany .
Jana E
JE
Lorenz
Wiebke
W
Kallenborn-Gerhardt
Ruirui
R
Lu
Katharina M J
KM
Syhr
Philip
P
Eaton
Gerd
G
Geisslinger
Achim
A
Schmidtko
D000818:Animals; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000378:metabolism*; D019281:Dimerization; D004789:Enzyme Activation; D051379:Mice; D009437:Neuralgia / Q000517:prevention & control*; D016877:Oxidants / Q000494:pharmacology*; D017933:Peripheral Nervous System / Q000293:injuries*
D016877:Oxidants; D062965:Cyclic GMP-Dependent Protein Kinase Type I