Oxidant-Induced Activation of cGMP-Dependent Protein Kinase Ia Mediates Neuropathic Pain After Peripheral Nerve Injury

Aims: 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 Ia (cGKIa), 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 cGKIa activation is increased in dorsal root ganglia of mice. Knock-in (KI) mice in which cGKIa 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. Innovation: Studying cGKIa KI mice, we provide the first evidence that oxidants activate cGKIa in sensory neurons after peripheral nerve injury in vivo. Conclusion: Our results suggest that oxidant-induced activation of cGKIa specifically contributes to neuropathic pain processing, and that prevention of cGKIa redox activation could be a potential novel strategy to manage neuropathic pain.