Publications by authors named "Katharina Metzner"

6 Publications

  • Page 1 of 1

Lack of efficacy of a partial adenosine A1 receptor agonist in neuropathic pain models in mice.

Purinergic Signal 2021 Jul 27. Epub 2021 Jul 27.

Institute of Pharmacology and Clinical Pharmacy, Goethe University Frankfurt, 60438, Frankfurt am Main, Germany.

Previous studies suggest that adenosine A receptors (AR) modulate the processing of pain. The aim of this study was to characterize the distribution of AR in nociceptive tissues and to evaluate whether targeting AR with the partial agonist capadenoson may reduce neuropathic pain in mice. The cellular distribution of AR in dorsal root ganglia (DRG) and the spinal cord was analyzed using fluorescent in situ hybridization. In behavioral experiments, neuropathic pain was induced by spared nerve injury or intraperitoneal injection of paclitaxel, and tactile hypersensitivities were determined using a dynamic plantar aesthesiometer. Whole-cell patch-clamp recordings were performed to assess electrophysiological properties of dissociated DRG neurons. We found AR to be expressed in populations of DRG neurons and dorsal horn neurons involved in the processing of pain. However, administration of capadenoson at established in vivo doses (0.03-1.0 mg/kg) did not alter mechanical hypersensitivity in the spared nerve injury and paclitaxel models of neuropathic pain, whereas the standard analgesic pregabalin significantly inhibited the pain behavior. Moreover, capadenoson failed to affect potassium currents in DRG neurons, in contrast to a full AR agonist. Despite expression of AR in nociceptive neurons, our data do not support the hypothesis that pharmacological intervention with partial AR agonists might be a valuable approach for the treatment of neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11302-021-09806-6DOI Listing
July 2021

Nox4-dependent upregulation of S100A4 after peripheral nerve injury modulates neuropathic pain processing.

Free Radic Biol Med 2021 05 28;168:155-167. Epub 2021 Mar 28.

Institute of Pharmacology and Clinical Pharmacy, Goethe University, 60438 Frankfurt am Main, Germany. Electronic address:

Previous studies suggested that reactive oxygen species (ROS) produced by NADPH oxidase 4 (Nox4) affect the processing of neuropathic pain. However, mechanisms underlying Nox4-dependent pain signaling are incompletely understood. In this study, we aimed to identify novel Nox4 downstream interactors in the nociceptive system. Mice lacking Nox4 specifically in sensory neurons were generated by crossing Advillin-Cre mice with Nox4 mice. Tissue-specific deletion of Nox4 in sensory neurons considerably reduced mechanical hypersensitivity and neuronal action potential firing after peripheral nerve injury. Using a proteomic approach, we detected various proteins that are regulated in a Nox4-dependent manner after injury, including the small calcium-binding protein S100A4. Immunofluorescence staining and Western blot experiments confirmed that S100A4 expression is massively up-regulated in peripheral nerves and dorsal root ganglia after injury. Furthermore, mice lacking S100A4 showed increased mechanical hypersensitivity after peripheral nerve injury and after delivery of a ROS donor. Our findings suggest that S100A4 expression is up-regulated after peripheral nerve injury in a Nox4-dependent manner and that deletion of S100A4 leads to an increased neuropathic pain hypersensitivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.freeradbiomed.2021.03.021DOI Listing
May 2021

Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Institut für Pharmakologie und Klinische Pharmazie, Goethe-Universität Frankfurt am Main, 60438 Frankfurt am Main, Hessen, Germany.

The sodium-activated potassium channel Slack (K1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22010405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795269PMC
January 2021

Neuropathic and cAMP-induced pain behavior is ameliorated in mice lacking CNGB1.

Neuropharmacology 2020 07 6;171:108087. Epub 2020 Apr 6.

Institute of Pharmacology and Clinical Pharmacy, Goethe University, 60438, Frankfurt am Main, Germany.

Cyclic nucleotide-gated (CNG) channels, which are directly activated by cAMP and cGMP, have long been known to play a key role in retinal and olfactory signal transduction. Emerging evidence indicates that CNG channels are also involved in signaling pathways important for pain processing. Here, we found that the expression of the channel subunits CNGA2, CNGA3, CNGA4 and CNGB1 in dorsal root ganglia, and of CNGA2 in the spinal cord, is transiently altered after peripheral nerve injury in mice. Specifically, we show using in situ hybridization and quantitative real-time RT-PCR that CNG channels containing the CNGB1b subunit are localized to populations of sensory neurons and predominantly excitatory interneurons in the spinal dorsal horn. In CNGB1 knockout (CNGB1) mice, neuropathic pain behavior is considerably attenuated whereas inflammatory pain behavior is normal. Finally, we provide evidence to support CNGB1 as a downstream mediator of cAMP signaling in pain pathways. Altogether, our data suggest that CNGB1-positive CNG channels specifically contribute to neuropathic pain processing after peripheral nerve injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2020.108087DOI Listing
July 2020

DPP10 is a new regulator of Nav1.5 channels in human heart.

Int J Cardiol 2019 06 3;284:68-73. Epub 2019 Jan 3.

Rudolf-Boehm-Institute of Pharmacology and Toxicology, Leipzig University, Leipzig, Germany; Department of Pharmacology and Toxicology, TU Dresden, Dresden, Germany. Electronic address:

Background: Cardiac accessory β-subunits are part of macromolecular Nav1.5 channel complexes modulating biophysical properties and contributing to arrhythmias. Recent studies demonstrated the structural interaction between β-subunits of Na (Nav1.5) and K (Kv4.3) channels. Here, we identified the dipeptidyl peptidase-like protein-10 (DPP10), which is known to modulate Kv4.3-current kinetics, as a new regulator of Nav1.5 channels.

Methods: We assessed DPP10 expression in the healthy and diseased human heart and we studied the functional effects of DPP10 on the Na current in isolated rat cardiomyocytes expressing DPP10 after adenoviral gene-transfer (DPP10ad).

Results: DPP10 mRNA and proteins were detected in human ventricle, with higher levels in patients with heart failure. In rat cardiomyocytes, DPP10ad significantly reduced upstroke velocity of action potentials indicating reduction in Na-current density. DPP10 significantly shifted the voltage-dependent Na channel activation and inactivation curve to more positive potentials, resulting in greater availability of Na channels for activation, along with increasing window Na current. In addition, time-to-peak Na current was reduced, whereas time course of recovery from inactivation was significantly accelerated by DPP10ad. DPP10 co-immunoprecipitated with Nav1.5 channels in human ventricles, confirming their physical interaction.

Conclusion: We provide first evidence that DPP10 interacts with Nav1.5 channels, linking Na- and K-channel complexes in the heart. Our data suggest that increased ventricular DPP10 expression in heart failure might promote arrhythmias by decreasing peak Na current, while increasing window Na current and channel re-openings due to accelerated recovery from inactivation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2018.12.072DOI Listing
June 2019

Arrhythmias, elicited by catecholamines and serotonin, vanish in human chronic atrial fibrillation.

Proc Natl Acad Sci U S A 2014 Jul 14;111(30):11193-8. Epub 2014 Jul 14.

Pharmacology, University of Murcia, 30100 Murcia, Spain

Atrial fibrillation (AF) is the most common heart rhythm disorder. Transient postoperative AF can be elicited by high sympathetic nervous system activity. Catecholamines and serotonin cause arrhythmias in atrial trabeculae from patients with sinus rhythm (SR), but whether these arrhythmias occur in patients with chronic AF is unknown. We compared the incidence of arrhythmic contractions caused by norepinephrine, epinephrine, serotonin, and forskolin in atrial trabeculae from patients with SR and patients with AF. In the patients with AF, arrhythmias were markedly reduced for the agonists and abolished for forskolin, whereas maximum inotropic responses were markedly blunted only for serotonin. Serotonin and forskolin produced spontaneous diastolic Ca(2+) releases in atrial myocytes from the patients with SR that were abolished or reduced in myocytes from the patients with AF. For matching L-type Ca(2+)-current (ICa,L) responses, serotonin required and produced ∼ 100-fold less cAMP/PKA at the Ca(2+) channel domain compared with the catecholamines and forskolin. Norepinephrine-evoked ICa,L responses were decreased by inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in myocytes from patients with SR, but not in those from patients with AF. Agonist-evoked phosphorylation by CaMKII at phospholamban (Thr-17), but not of ryanodine2 (Ser-2814), was reduced in trabeculae from patients with AF. The decreased CaMKII activity may contribute to the blunting of agonist-evoked arrhythmias in the atrial myocardium of patients with AF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1324132111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121801PMC
July 2014
-->