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