Dr. Stefan Lechner

Institute of Pharmacology, Medical Faculty Heidelberg, Heidelberg University

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

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.

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 R, McMahon S, Schmelz M, Rukwied R. Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain. Ann Neurol 2018;83:945-957.

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.

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.

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.

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.

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

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.

 

News

  • Preparatory Retreat

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  • Upcoming ICD-11 Classification of Chronic Pain

    The upcoming ICD-11 Classification of Chronic Pain is featured in Pain Research Forum

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  • Annual International Research Symposium 2018

    Annual International Research Symposium 2018

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  • PHOENIX Science Award 2018

    Rohini Kuner honoured with Phoenix Science Award

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  • Young scientists honoured at Pain Congress

    At the German Pain Congress (Deutscher Schmerzkongress), SFB Scientist  Linette Tan (B01) was honored with this year's prize for basic science. Other scientists working in the Heidelberg Pain Consortium also received prizes.

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