Painful stimuli are detected by sensory neurons whose cell somata are located in dorsal root ganglia and trigeminal ganglia. Upon activation, they conduct nociceptive sensory information from peripheral sites to the dorsal horn of the spinal cord, where they form synapses with spinal neurons. Previous studies in our and other labs revealed that pain processing is associated with cGMP production in sensory and spinal neurons. However, the in vivo functions of cGMP in pain processing are poorly understood. Using conditional knockout mice we will investigate the functional role of cGMP signalling pathways during chronic pain induced by sciatic nerve crush injury, a model that involves degeneration and regeneration of primary afferent neurons. In particular, we will characterize the localization of cGMP generators and cGMP effectors, the spatiotemporal dynamics of cGMP production after painful stimulation, and downstream mechanisms of cGMP signalling. Altogether, this project will provide more information on how different cGMP signalling pathways contribute to pain processing and regeneration after nerve injury. The long-term goal is to find out whether targeting cGMP signalling could serve as a new approach for treatment of chronic pain.
PI of this project; PIs of other FOR 2060 projects are in bold.
1. Lu R, Bausch A, Kallenborn-Gerhardt W, Stoetzer C, Debruin N, Ruth P, Geisslinger G, Leffler A, Lukowski R, Schmidtko A. Slack channels expressed in sensory neurons control neuropathic pain in mice. J Neurosci. 2015;35:1125-35 [Project 5] [Project 10] [pubmed]
2. Lorenz JE, Kallenborn-Gerhardt W, Lu R, Syhr KM, Eaton P, Geisslinger G, Schmidtko A. Oxidant-induced activation of cGMP-dependent protein kinase Iα mediates neuropathic pain after peripheral nerve injury. Antioxid Redox Signal. 2014;21:1504-15 [Project 10] [pubmed]
3. Kallenborn-Gerhardt W, Lu R, Bothe A, Thomas D, Schlaudraff J, Lorenz JE, Lippold N, Real CI, Ferreirós N, Geisslinger G, Del Turco D, Schmidtko A. Phosphodiesterase 2A localized in the spinal cord contributes to inflammatory pain processing. Anesthesiology. 2014;121:372-82 [Project 10] [pubmed]
4. Lu R, Lukowski R, Sausbier M, Zhang DD, Sisignano M, Schuh CD, Kuner R, Ruth P, Geisslinger G, Schmidtko A. BKCa channels expressed in sensory neurons modulate inflammatory pain in mice. Pain. 2014;155:556-65 [Project 5] [Project 10] [pubmed]
5. Kallenborn-Gerhardt W, Lu R, Syhr KM, Heidler J, von Melchner H, Geisslinger G, Bangsow T, Schmidtko A. Antioxidant activity of Sestrin 2 controls neuropathic pain after peripheral nerve injury. Antioxid Redox Signal. 2013;19:2013-23 [Project 10] [pubmed]
6. Kallenborn-Gerhardt W, Schröder K, Del Turco D, Lu R, Kynast K, Kosowski J, Niederberger E, Shah AM, Brandes RP, Geisslinger G, Schmidtko A. NADPH oxidase-4 maintains neuropathic pain after peripheral nerve injury. J Neurosci. 2012;32:10136-45 [Project 10] [pubmed]
7. Heine S, Michalakis S, Kallenborn-Gerhardt W, Lu R, Lim H, Weiland J, Del Turco D, Deller T, Tegeder I, Biel M, Geisslinger G, Schmidtko A. CNGA3: A target of spinal NO/cGMP signaling and modulator of inflammatory pain hypersensitivity. J Neurosci. 2011;31:11184-92 [Project 10] [pubmed]
9. Schmidtko A, Gao W, König P, Heine S, Motterlini R, Ruth P, Schlossmann J, Koesling D, Niederberger E, Tegeder I, Friebe A, Geisslinger G. cGMP produced by NO-sensitive guanylyl cyclase essentially contributes to inflammatory and neuropathic pain by using targets different from cGMP-dependent protein kinase I. J Neurosci. 2008;28:8568-76 [Project 2] [Project 3] [Project 5] [Project 10] [pubmed]
10. Schmidtko A, Gao W, Sausbier M, Rauhmeier I, Sausbier U, Niederberger E, Scholich K, Huber A, Neuhuber W, Allescher HD, Hofmann F, Tegeder I, Ruth P, Geisslinger G. Cysteine-rich protein 2, a novel downstream effector of cGMP/cGMP-dependent protein kinase I-mediated persistent inflammatory pain. J Neurosci. 2008;28:1320-30 [Project 5] [Project 10] [pubmed]