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

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"

Prolonged zymosan-induced inflammatory pain hypersensitivity in mice lacking glycine receptor alpha2

Glycinergic synapses play a major role in shaping the activity of spinal cord neurons under normal conditions and during persistent pain. However, the role of different glycine receptor (GlyR) subtypes in pain processing has only begun to be unraveled. Here, we analysed whether the GlyR alpha2 subunit might be involved in the processing of acute or persistent pain. Real-time RT-PCR and in situ hybridization analyses revealed that GlyR alpha2 mRNA is enriched in the dorsal horn of the mouse spinal cord. Mice lacking GlyR alpha2 (Glra2(-/-) mice) demonstrated a normal nociceptive behavior in models of acute pain and after peripheral nerve injury. However, mechanical hyperalgesia induced by peripheral injection of zymosan was significantly prolonged in Glra2(-/-) mice as compared to wild-type littermates. We conclude that spinal GlyRs containing the alpha2 subunit exert a previously unrecognized role in the resolution of inflammatory pain

Slack Channels Expressed in Sensory Neurons Control Neuropathic Pain in Mice

Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that modulating its activity might represent a novel strategy for management of neuropathic pain

Rab7 - A novel redox target that modulates inflammatory pain processing

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity