People:

Kiran Bali (Kiran.Bali(at)medma.uni-heidelberg.de)

Marc Behrendt (marc.behrendt(at)medma.uni-heidelberg.de)

Sabrina da Silva Soares (Sabrina.Soares(at)medma.uni-heidelberg.de)

Timo Nees (timo.nees(at)pharma.uni-heidelberg.de)

Jürgen Solinski (Juergen.Solinski(at)medma.uni-heidelberg.de)

Clement Verkest (clement.verkest(at)pharma.uni-heidelberg.de)

 

New collaborations:

Angelika Lampert (Aachen) – pig DRG and iPSC-nociceptors

 

New appointments:

Prof. Dr. Martin Schmelz has been elected as first chair of the new IASP SIG on itch in April 2021.

Prof. Dr. Stefan Lechner has accepted a Full Professor position (Professor for Experimental Anaesthesiology) at the UKE Hamburg.

Prof. Dr. Stefan Lechner

Center for Anesthesiology and Intensive Care Medicine, University Medical Center Hamburg-Eppendorf

Prof. Dr. Martin Schmelz

Department of Experimental Pain Research, Medical Faculty Mannheim, Heidelberg University

 

Structure-function properties and markers of silent nociceptors in mice and humans

This project will focus on mechano-insensitive nociceptors, which become sensitized during inflammation. We have identified a molecular marker for these so-called ‘silent’ nociceptors, which for the first time enables us to thoroughly characterize the functional properties of these afferents and the signalling cascades that mediate sensitization during inflammation as well as their role in the induction and maintenance of mechanical hyperalgesia under pathological conditions. To this end we will utilize intersectional genetics (cell ablation, optogenetics and DREADD technology) in combination with electrophysiological techniques (patch-clamp, in-vitro skin-nerve recordings and spinal cord slice recordings) and behavioural assays.

An important goal of this project is to test the clinical relevance of results obtained from experiments in mice in human studies.

Hence, in corresponding human experiments characteristics of silent nociceptors and their sensitization by inflammatory mediators will be studied using microneurography and psychophysics to allow for bidirectional translation. Based on functional differences of nociceptor classes, specific excitability tests are being developed that work on single cell level, but also in ex-vivo preparations of peripheral nerves and in human volunteers and pain patients. The long-term perspective of this project is the identification of specific targets on silent nociceptors that enable control of their excitability in order to provide new analgesic approaches in animal models and finally in pain patients.

Publications

Landmann G, Stockinger L, Gerber B, Benrath J, Schmelz M, Rukwied R. Local hyperexcitability of C-nociceptors may predict responsiveness to topical lidocaine in neuropathic pain. PLoS One 2022;17:e0271327

Verkest C, Schaefer I, Nees TA, Wang N, Jegelka JM, Taberner FJ, Lechner SG. Intrinsically disordered intracellular domains control key features of the mechanically-gated ion channel PIEZO2. Nat Commun 2022;13:1365

Fryk E, Olausson J, Mossberg K, Strindberg L, Schmelz M, Brogren H, Gan LM, Piazza S, Provenzani A, Becattini B, Lind L, Solinas G, Jansson PA. Hyperinsulinemia and insulin resistance in the obese may develop as part of a homeostatic response to elevated free fatty acids: A mechanistic case-control and a population-based cohort study. EBioMedicine. 2021;65:103264.

Schnakenberg M, Thomas C, Schmelz M, Rukwied R. Nerve growth factor sensitizes nociceptors to C-fibre selective supra-threshold electrical stimuli in human skin. Eur J Pain. 2021;25(2):385-97.

Morelli, C., Castaldi, L., Brown, S.J., Streich, L.L., Websdale, A., Taberner, F.J., Cerreti, B., Barenghi, A., Blum, K.M., Sawitzke, J., Frank, T., Steffens, L.K., Doleschall, B., Serrao, J., Ferrarini, D., Lechner, S.G., Prevedel, R., Heppenstall, P.A., 2021. Identification of a population of peripheral sensory neurons that regulates blood pressure. Cell Rep 35, 109191. https://doi.org/10.1016/j.celrep.2021.109191

Schwaller, F., Bégay, V., García-García, G., Taberner, F.J., Moshourab, R., McDonald, B., Docter, T., Kühnemund, J., Ojeda-Alonso, J., Paricio-Montesinos, R., Lechner, S.G., Poulet, J.F.A., Millan, J.M., Lewin, G.R., 2021. USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans. Nat Neurosci 24, 74–81. https://doi.org/10.1038/s41593-020-00751-y

Narayanan, P., Hütte, M., Kudryasheva, G., Taberner, F.J., Lechner, S.G., Rehfeldt, F., Gomez-Varela, D., Schmidt, M., 2018. Myotubularin related protein-2 and its phospholipid substrate PIP2control Piezo2-mediated mechanotransduction in peripheral sensory neurons. Elife 7. https://doi.org/10.7554/eLife.32346

Schmelz M. What can we learn from the failure of quantitative sensory testing? Pain. 2021;162(3):663-4.

Werland F, de Col R, Hirth M, Turnquist B, Schmelz M, Obreja O. Mechanical sensitization, increased axonal excitability, and spontaneous activity in C-nociceptors after ultraviolet B irradiation in pig skin. Pain. 2021;162(7):2002-13.

Werland F, Hirth M, Rukwied R, Ringkamp M, Turnquist B, Jorum E, Namer B, Schmelz M, Obreja O. Maximum axonal following frequency separates classes of cutaneous unmyelinated nociceptors in the pig. J Physiol. 2021;599(5):1595-610.

Davids M, Guerin B, Klein V, Schmelz M, Schad LR, Wald LL. Optimizing selective stimulation of peripheral nerves with arrays of coils or surface electrodes using a linear peripheral nerve stimulation metric. J Neural Eng. 2020;17(1):016029.

Kokotis P, Manios E, Schmelz M, Fotiou D, Dialoupi I, Gavriatopoulou M, Roussou M, Lykka A, Dimopoulos MA, Kastritis E. Involvement of small nerve fibres and autonomic nervous system in AL amyloidosis: comprehensive characteristics and clinical implications. Amyloid. 2020;27(2):103-10.

Meents JE, Bressan E, Sontag S, Foerster A, Hautvast P, Rosseler C, Hampl M, Schuler H, Goetzke R, Le TKC, Kleggetveit IP, Le Cann K, Kerth C, Rush AM, Rogers M, Kohl Z, Schmelz M, Wagner W, Jorum E, Namer B, Winner B, Zenke M, Lampert A. The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell-derived sensory neurons of erythromelalgia patients. Pain. 2019;160(6):1327-41.

Schmelz M, Mantyh P, Malfait AM, Farrar J, Yaksh T, Tive L, Viktrup L. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain. 2019;160(10):2210-20. (review)

Dhandapani R, Arokiaraj CM, Taberner FJ, Pacifico P, Raja S, Nocchi L, Portulano C, Franciosa F, Maffei M, Hussain AF, de Castro Reis F, Reymond L, Perlas E, Garcovich S, Barth S, Johnsson K, Lechner SG, Heppenstall PA. Control of mechanical pain hypersensitivity in mice through ligand-targeted photoablation of TrkB-positive sensory neurons. Nat Commun 2018;9:1640.

Jonas R, Namer B, Stockinger L, Chisholm K, Schnakenberg M, Landmann G, Kucharczyk M, Konrad C, Schmidt R, Carr RW, McMahon S, Schmelz M, Rukwied R. Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain. Ann Neurol 2018;83:945-957.

Klusch A, Gorzelanny C, Reeh PW, Schmelz M, Petersen M, Sauer SK. Local NGF and GDNF levels modulate morphology and function of porcine DRG neurites, In Vitro. PLoS ONE. 2018;13(9):e0203215.

Obreja O, Rukwied R, Nagler L, Schmidt M, Schmelz M, Namer B. Nerve growth factor locally sensitises nociceptors in human skin. PAIN 2018;159(3):416-426.

Sauerstein K, Liebelt J, Namer B, Schmidt R, Rukwied R, Schmelz M. Low-Frequency Stimulation of Silent Nociceptors Induces Secondary Mechanical Hyperalgesia in Human Skin. NEUROSCIENCE 2018; 387:4-12.

Schäfer I, Prato V, Arcourt A, Taberner FJ, Lechner SG. Differential modulation of voltage-gated sodium channels by nerve growth factor in three major subsets of TrkA-expressing nociceptors. Mol Pain 2018

Arcourt A, Gorham L, Dhandapani R, Prato V, Taberner FJ, Wende H, Gangadharan V, Birchmeier C, Heppenstall PA, Lechner SG. Touch Receptor-Derived Sensory Information Alleviates Acute Pain Signaling and Fine-Tunes Nociceptive Reflex Coordination. Neuron 2017;93:179–193.

Klein AH, Vyshnevska A, Hartke TV, De Col R, Mankowski JL, Turnquist B, Bosmans F, Reeh PW, Schmelz M, Carr RW, Ringkamp M. Sodium Channel Nav1.8 Underlies TTX-Resistant Axonal Action Potential Conduction in Somatosensory C-Fibers of Distal Cutaneous Nerves. J NEUROSCI 2017;37(20):5204-5214.

Prato V, Taberner FJ, Hockley JRF, Callejo G, Arcourt A, Tazir B, Hammer L, Schad P, Heppenstall PA, Smith ES, Lechner SG. Functional and Molecular Characterization of Mechanoinsensitive “Silent” Nociceptors. Cell Reports 2017;21:3102–3115.

Namer B, Ørstavik K, Schmidt R, Kleggetveit I-P, Weidner C, Mørk C, Kvernebo MS, Kvernebo K, Salter H, Carr TH, Segerdahl M, Quiding H, Waxman SG, Handwerker HO, Torebjörk HE, Jørum E, Schmelz M. Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7. Pain 2015;156:1637–1646.

Schrenk-Siemens K, Wende H, Prato V, Song K, Rostock C, Loewer A, Utikal J, Lewin GR, Lechner SG, Siemens J. PIEZO2 is required for mechanotransduction in human stem cell-derived touch receptors. Nat Neurosci 2015;18:10–16.


Joint publications:

Bali KK, Gandla J, Rangel DR, Castaldi L, Mouritzen P, Agarwal N, Schmelz M, Heppenstall P, Kuner R. A genome-wide screen reveals microRNAs in peripheral sensory neurons driving painful diabetic neuropathy. Pain. 2021;162(5):1334-51.

Bonalume V, Caffino L, Castelnovo LF, Faroni A, Liu S, Hu J, Milanese M, Bonanno G, Sohns K, Hoffmann T, De Col R, Schmelz M, Fumagalli F, Magnaghi V, Carr RW. Axonal GABAA stabilises excitability in unmyelinated sensory axons secondary to NKCC1 activity. J Physiol. 2021 (in press).

Bonalume V, Caffino L, Castelnovo LF, Faroni A, Giavarini F, Liu S, Caruso D, Schmelz M, Fumagalli F, Carr RW, Magnaghi V. Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCepsilon in Peripheral Sensory Neurons. Cells. 2020;9(8).

Jonas R, Prato V, Lechner SG, Groen G, Obreja O, Werland F, Rukwied R, Klusch A, Petersen M, Carr RW, Schmelz M. TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors. Front Cell Neurosci. 2020;14(13):13.

Agarwal, N., Taberner, F.J., Rangel Rojas, D., Moroni, M., Omberbasic, D., Njoo, C., Andrieux, A., Gupta, P., Bali, K.K., Herpel, E., Faghihi, F., Fleming, T., Dejean, A., Lechner, S.G., Nawroth, P.P., Lewin, G.R., Kuner, R., 2020. SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes. Neuron 107, 1141-1159.e7. https://doi.org/10.1016/j.neuron.2020.06.037

Jonas, R., Prato, V., Lechner, S.G., Groen, G., Obreja, O., Werland, F., Rukwied, R., Klusch, A., Petersen, M., Carr, R.W., Schmelz, M., 2020. TTX-Resistant Sodium Channels Functionally Separate Silent From Polymodal C-nociceptors. Front Cell Neurosci. 2020 Feb 7;14:13. doi: 10.3389/fncel.2020.00013. eCollection 2020. PMID: 32116559 https://doi.org/10.3389/fncel.2020.00013

Jonas R, Namer B, Schnakenberg M, Soares S, Pakalniskis J, Carr R, Schmelz M, Rukwied R. Sympathetic efferent neurons are less sensitive than nociceptors to 4 Hz sinusoidal stimulation. Eur J Pain. 2020;24(1):122-33.

Liu H, Andoh J, Lyu Y, Milde C, Desch S, Zidda F, Schmelz M, Curio G, Flor H. Peripheral input and phantom limb pain: A somatosensory event-related potential study. Eur J Pain. 2020;24(7):1314-29.

Rukwied R, Thomas C, Obreja O, Werland F, Kleggetveit IP, Jorum E, Carr RW, Namer B, Schmelz M. Slow depolarizing stimuli differentially activate mechanosensitive and silent C nociceptors in human and pig skin. Pain. 2020;161(9):2119-28.


Other publications:

Nees TA, Wang N, Adamek P, Verkest C, La Porta C., Schaefer I, Virnich J, Balkaya S, Prato V, Morelli C, Zeitzschel N, Begay V, Lee YJ, Tappe-Theodor A., Lewin GR, Heppenstall PA, Taberner FJ, Lechner SG. The molecular mechanism and physiological role of silent nociceptor activation. bioRxiv.2022.2004.2007.486730, 2022; DOI: https://doi.org/10.1101/2022.04.07.486730, also in revision at Nat. Commun.

Stander S, Schmelz M. [Neuropathic pruritus]. Schmerz. 2020;34(6):525-35.

Taberner, F.J., Prato, V., Schaefer, I., Schrenk-Siemens, K., Heppenstall, P.A., Lechner, S.G., 2019. Structure-guided examination of the mechanogating mechanism of PIEZO2. Proc. Natl. Acad. Sci. U.S.A. 116, 14260–14269. https://doi.org/10.1073/pnas.1905985116

Dusch M, Schmelz M. [Erythromelalgia: skin redness and pain]. Schmerz. 2019;33(5):475-90.

Steinhoff M, Oaklander AL, Szabo IL, Stander S, Schmelz M. Neuropathic itch. Pain. 2019;160 Suppl 1:S11-S6. (review)

Steinhoff M, Schmelz M, Szabo IL, Oaklander AL. Clinical presentation, management, and pathophysiology of neuropathic itch. Lancet Neurol. 2018;17(8):709-20. (review)

 

News

  • New collaborative research results

    Published in Science

     

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  • ERC Synergy Grant 2022

    Congratulations to Prof. Dr. Valery Grinevich!

     

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  • John J. Bonica Prize of the IASP

    Congratulations to Prof. Dr. Rolf Detlef-Treede!

     

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  • New paper published in Nature

    Collaboration involving Projects A01, A03, B01, B06 and B08.

     

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  • Pain Summer School

    "Chronic Pain and its affective consequences"

     

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