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Oxidant-induced activation of cGMP-dependent protein kinase Iα contributes to neuropathic pain processing after nerve injury

: Kallenborn-Gerhardt, W.; Lorenz, J.E.; Lu, R.; Eaton, P.; Geisslinger, G.; Schmidtko, A.

Naunyn-Schmiedebergs archives of pharmacology 387 (2014), Supplement, S.S55
ISSN: 0028-1298
ISSN: 1432-1912
Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie (Annual Meeting) <80, 2014, Hannover>
Fraunhofer IME ()

Lesions or damage to the peripheral or central nervous system induce changes in the nociceptive system that are often accompanied with neuropathic pain. Treatment of neuropathic pain can be difficult with only 40-60% of patients achieving potential pain relief. Several signaling pathways have been identified that are involved in the processing of pain. Recent data indicate that oxidants such as hydrogen peroxide exert specific signaling functions during the processing of neuropathic pain. However, the mechanisms by which oxidants regulate pain processing in vivo remain poorly understood. Here, we show that cGMP-dependent protein kinase Iα (cGKIα), which can be activated by oxidants independently of cGMP, serves as a primary redox target in sensory neurons. After peripheral nerve injury, oxidant-induced cGKIα activation is increased in dorsal root ganglia of mice. cGKIα knock-in mice, in which the oxidant mediated activation of cGKIα is blocked, demonstrated reduced neuropathic pain behavior after injury to peripheral nerves, while acute nociceptive, inflammatory, and cGMP-induced pain behaviors were not impaired in these mice. Our results suggest that oxidant-induced activation of cGKIα specifically contributes to neuropathic pain processing in vivo. Prevention of cGKIα redox activation could be a potential novel strategy to manage neuropathic pain.
Acknowledgements: This work was supported by the Deutsche Forschungsgemeinschaft (SFB815-A14) and in part by LOEWE-Schwerpunkt "Anwendungsorientierte Arzneimittelforschung".