cGMP signalling in pain processing and regeneration after peripheral nerve injury

Achim Schmidtko, Frankfurt

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.

Fig. 1. Suggested NO and cGMP signaling pathways during spinal pain sensitization. In the dorsal horn of the spinal cord, NO-GC is localized to inhibitory interneurons and to lamina I neurons that express the substance P receptor NK1 (NK1-R) projecting to supraspinal areas of the nociceptive system. At rest, nNOS is expressed in some inhibitory interneurons and in <5% of primary afferent neurons. During inflammatory and neuropathic pain, nNOS is activated and upregulated in inhibitory interneurons and in primary afferent neurons, respectively. The increased NO production leads to activation of NO-GC and subsequent cGMP production in NO-GC-expressing neurons. In contrast to NO-GC, cGMP-dependent protein kinase I (cGKI, α isoform) is mainly expressed in primary afferent neurons. Recent evidence indicates that during nociceptive processing cGKI is activated by cGMP produced by the ‘particulate’ guanylyl cyclase natriuretic peptide receptor B (NPR-B) upon stimulation by C-natriuretic peptide (CNP). Cysteine-rich protein 4 (CRP4) has an inhibitory role in the generation of inflammatory pain and is a downstream effector of cGKI. A possible contribution of CRP4 to nociceptive processing might be an inhibitory effect of CRP4 on pronociceptive pathways under resting conditions and the cessation of this inhibitory effect during the processing of pain sensitization that includes phosphorylation of CRP4 by cGKI. Solid and dashed lines indicate direct and indirect interactions, respectively. Schmidtko et al., Trends Neurosci., 2009;32:339-46 (C) Achim Schmidtko

Project-related publications

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]

8.    Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet. 2010;375:1569-77  [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]