cGMP signaling in pain processing and regeneration after peripheral nerve injury

• Applicant: Professor Dr. Achim Schmidtko
• Subject Area: Pharmacology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 427878057

• Final Report Year: 2024

Final Report Abstract

Chronic pain is a highly prevalent and poorly managed health problem. Unraveling the molecular mechanisms underlying pain processing is a crucial prerequisite for the targeted development of novel analgesic drugs. Previous studies in our and other labs revealed that pain processing is associated with production of the second messenger cyclic guanosine monophosphate (cGMP) in the nociceptive system. There is accumulating evidence that cGMP production during chronic pain is not only initiated by nitric oxide (NO) but also by natriuretic peptides (NP). However, the cellular distribution and the functional impact of NO- and NP- dependent cGMP production in this context remains poorly understood. The major aim of this project was the functional characterization of different cGMP signaling pathways in the nociceptive system. We found that the two isoforms of the NO-sensitive guanylyl cyclase (GC-1 and GC-2) are localized to distinct populations of interneurons in the dorsal horn of the spinal cord. Interestingly, GC-1 is involved in the processing of neuropathic pain after peripheral nerve injury, whereas GC-2 modulates the processing of inflammatory pain. Furthermore, we observed that NP control the cGMP production in neuronal populations of the nociceptive system, and are important both in acute nociceptive pain and in the sensitization of pain pathways. The results of this project led to the conclusion that different cGMP signaling pathways controlled by NO and NP in the nociceptive system are functionally involved in the processing of acute, inflammatory and neuropathic pain. The findings of this project could therefore provide the basis for novel pharmacological pain therapy in future.

Publications

• Distinct functions of NO-GC1 and NO-GC2 in the processing of neuropathic and inflammatory pain. 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications 2017, Bamberg
  Petersen J.; Kennel L.; Mergia E.; Drees O.; Lu R.; Real C.; Friebe A.; Koesling D. & Schmidtko A.
  
• KCa3.1 channels modulate the processing of noxious chemical stimuli in mice. Neuropharmacology, 125, 386-395.
  Lu, Ruirui; Flauaus, Cathrin; Kennel, Lea; Petersen, Jonas; Drees, Oliver; Kallenborn-Gerhardt, Wiebke; Ruth, Peter; Lukowski, Robert & Schmidtko, Achim
  
• cGMP Imaging in Brain Slices Reveals Brain Region-Specific Activity of NO-Sensitive Guanylyl Cyclases (NO-GCs) and NO-GC Stimulators. International Journal of Molecular Sciences, 19(8), 2313.
  Peters, Stefanie; Paolillo, Michael; Mergia, Evanthia; Koesling, Doris; Kennel, Lea; Schmidtko, Achim; Russwurm, Michael & Feil, Robert
  
• cGMP-dependent signaling pathways in chronic pain processing. DPhG Annual Meeting 2018, Hamburg.
  Petersen J.; Mergia E.; Kennel L.; Drees O.; Steubing R.; Real C.; Kallenborn-Gerhardt W.; Lu R.; Friebe A.; Koesling D. & Schmidtko A.
  
• cGMP-dependent signaling pathways in chronic pain processing. Hot Topics in Signal Transduction & cGMP Research 2018, Tübingen
  Schmidtko A.
  
• Distinct functions of soluble guanylyl cyclase isoforms NO-GC1 and NO-GC2 in inflammatory and neuropathic pain processing. Pain, 160(3), 607-618.
  Petersen, Jonas; Mergia, Evanthia; Kennel, Lea; Drees, Oliver; Steubing, Rebecca Dorothee; Real, Catherine Isabell; Kallenborn-Gerhardt, Wiebke; Lu, Ruirui; Friebe, Andreas; Koesling, Doris & Schmidtko, Achim
  
• Mechanisms of cystein-rich protein 4 dependent pain processing. German Pharm- Tox Summit 2018, Göttingen.
  Kennel L.; Petersen J.; Flauaus C.; Drees O.; Schmidt H.; Ruth P.; Lukowski R. & Schmidtko A.
  
• The Absence of Sensory Axon Bifurcation Affects Nociception and Termination Fields of Afferents in the Spinal Cord. Frontiers in Molecular Neuroscience, 11.
  Tröster, Philip; Haseleu, Julia; Petersen, Jonas; Drees, Oliver; Schmidtko, Achim; Schwaller, Frederick; Lewin, Gary R.; Ter-Avetisyan, Gohar; Winter, York; Peters, Stefanie; Feil, Susanne; Feil, Robert; Rathjen, Fritz G. & Schmidt, Hannes
  
• Characterization of Cyclic Nucleotide Phosphodiesterases Potentially Involved in Pain Processing. 9th International Conference on cGMP Generators, Effectors and Therapeutic Implications 2019, Mainz
  Gross T.; Petersen J.; Kennel L.; Schlaudraff J.; Del Turco D.; Lu R.; Kallenborn-Gerhardt W. & Schmidtko A.
  
• Characterization of Cyclic Nucleotide Phosphodiesterases Potentially Involved in Pain Processing. German Pharm-Tox Summit 2019, Stuttgart.
  Gross T.; Petersen J.; Kennel L.; Schlaudraff J.; Del Turco D.; Lu R.; Kallenborn-Gerhardt W. & Schmidtko A.
  
• Distinct functions of NO-GC isoforms in the processing of chronic pain. The Challenge of Chronic Pain 2019, Hinxton, Cambridge, UK.
  Petersen J.; Mergia E.; Kennel L.; Drees O.; Steubing R.; Real C.; Kallenborn-Gerhardt W.; Lu R.; Friebe A.; Koesling D. & Schmidtko A.
  
• Specific functions of guanylyl cyclase-B in pain processing. 9th International Conference on cGMP Generators, Effectors and Therapeutic Implications 2019, Mainz.
  Kennel L.; Isensee J.; Petersen J.; Gross T.; Flauaus C.; Lu R.; Adler J.; Ruth P.; Hucho T.; Lukowski R.; Schmidt H. & Schmidtko A.
  
• Two isoforms of soluble guanylyl cyclase exert distinct functions in inflammatory and neuropathic pain processing. Keystone Symposium Mammalian Sensory Systems 2019, Seattle, Washington, USA.
  Petersen J.; Mergia E.; Kennel L.; Drees O.; Gross T.; Steubing R.; Real C.; Kallenborn-Gerhardt W.; Lu R.; Friebe A.; Koesling D. & Schmidtko A.
  
• Neuropathic and cAMP-induced pain behavior is ameliorated in mice lacking CNGB1. Neuropharmacology, 171, 108087.
  Kallenborn-Gerhardt, Wiebke; Metzner, Katharina; Lu, Ruirui; Petersen, Jonas; Kuth, Miriam S.; Heine, Sandra; Drees, Oliver; Paul, Mandy; Becirovic, Elvir; Kennel, Lea; Flauaus, Cathrin; Gross, Tilman; Wack, Gesine; Hohmann, Stephan W.; Nemirovski, Dina; Del Turco, Domenico; Biel, Martin; Geisslinger, Gerd; Michalakis, Stylianos & Schmidtko, Achim
  
• cGMP signalling in dorsal root ganglia and the spinal cord: Various functions in development and adulthood. British Journal of Pharmacology, 179(11), 2361-2377.
  Schmidt, Hannes; Böttcher, Alexandra; Gross, Tilman & Schmidtko, Achim
  
• Distinct functions of natriuretic peptide receptor 2 in pain processing. 10th International Conference on cGMP Generators, Effectors and Therapeutic Implications 2022, Augsburg.
  Gernighaus H.; Kennel L.; Kaiser A.; Zhou F.; Gross T.; Flauaus C.; Petersen J.; Kallenborn- Gerhardt W.; Schmidt H. & Schmidtko A.
  
• Functions of phosphodiesterases in pain processing. Gordon Research Conference Cyclic Nucleotide Phosphodiesterases 2022, Les Diablerets, Switzerland.
  Schmidtko A.
  
• Natriuretic peptide receptor 2/cGMP signaling in DRG neurons contributes to acute and chronic pain processing in mice. IASP World Congress on Pain 2022 Toronto, Canada.
  Gernighaus H.; Kennel L.; Kaiser A.; Zhou F.; Gross T.; Flauaus C.; Petersen J.; Kallen-born- Gerhardt W.; Schmidt H. & Schmidtko A.
  
• Slick Potassium Channels Control Pain and Itch in Distinct Populations of Sensory and Spinal Neurons in Mice. Anesthesiology, 136(5), 802-822.
  Flauaus, Cathrin; Engel, Patrick; Zhou, Fangyuan; Petersen, Jonas; Ruth, Peter; Lukowski, Robert; Schmidtko, Achim & Lu, Ruirui
  
• NO-sensitive guanylyl cyclase discriminates pericyte-derived interstitial from intra-alveolar myofibroblasts in murine pulmonary fibrosis. Respiratory Research, 24(1).
  Aue, Annemarie; Englert, Nils; Harrer, Leon; Schwiering, Fabian; Gaab, Annika; König, Peter; Adams, Ralf; Schmidtko, Achim; Friebe, Andreas & Groneberg, Dieter