Background & Aims

Recent studies have shown that reactive oxygen species (ROS) and cyclic guanosine monophosphate (cGMP) signaling in sensory neurons play an important role in the processing of pain. An important cGMP and redox target in the nociceptive system is cGMP-dependent protein kinase I? (PKG1?), which in addition to its cGMP-driven activation, can be oxidized at specific cysteine residues, leading to an active dimeric state. In this study, we investigated the functional role of redox-dependent activation of PKG1? in pain processing using a global PKG1? knock-in (KI) mouse model, in which the oxidant-induced activation via cysteine 42 is prevented, while its cGMP-dependent activity is unaltered.

Methods

We conducted immunohistochemistry, in situ hybridization, and qRT-PCR experiments to examine the expression pattern of PKG1? in dorsal root ganglia (DRG) neurons. Furthermore, we assessed the functional role of PKG1? and its redox-dependent activation in different animal models of pain behavior and ex vivo assays in primary neuronal DRG cultures, including ROS production assay and calcium imaging experiments.

Results

Our findings revealed a widespread distribution of PKG1? in DRG neurons and co-expression with major pain sensors. PKG1?-KI mice showed altered behavior in animal models of acute nociceptive and neuropathic pain. Stimulation of primary DRG neuron cultures with noxious compounds resulted in increased ROS production. Furthermore, calcium imaging experiments in cultured DRG neurons of PKG1?-KI mice revealed altered calcium influx after noxious stimulation.

Conclusions

Our data suggest that the oxidant-induced activation of PKG1? plays a crucial role in the processing of acute nociceptive pain. Further investigations are needed to elucidate up- and downstream mechanisms of this pathway and the specific function of ROS in pain processing.

References

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Presenting Author

Tim Berg

Poster Authors

Tim Berg

MSc

Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt

Lead Author

Nabil Bahrami (Master of Science)

Lead Author

Jonas Petersen (PhD)

Lead Author

Fangyuan Zhou (PhD)

Lead Author

Elena Wang (Master of Science)

Lead Author

Maximilian Koch (Master of Science)

Lead Author

Phillip Eaton (Prof. Dr.)

Lead Author

Achim Schmidtko

Goethe University Frankfurt

Lead Author

Wiebke Kallenborn-Gerhardt

Institute of Pharmacology and Clinical Pharmacy

Lead Author

Topics

  • Models: Acute Pain