Schmerzforschung in der Anästhesie

Anästhesie

Direktor:
Prof. Dr. med. Dr. h. c. Jürgen Schüttler

Leitung: Prof. Dr. Katharina Zimmermann

Research in the Zimmermann Lab at the Department of Anesthesiology at Friedrich-Alexander University Erlangen-Nürnberg focusses on the physiological role of ion channels in the somatosensory system. This relates to delineating the function of ion channels in thermo- and nociceptive transduction and electrogenesis as well as in the related pathophysiology.

Overview of some important past and present work

Reproduced with permission from JGP.
(Journal of General Physiology, Volume 150, Issue 8, 6 August 2018)

The NaV1.8 sodium channel subtype functions as cold-resistant ignition on nociceptors and is also able to shape heat-resistant action potentials above 45°C. Unlike other fast-gated and low-threshold sodium channel subtypes that become inactivated by cold or hot temperatures, Nav1.8 appears resistant and increases the excitability of nociceptors at noxious cold and hot temperatures. Nav1.9, in contrast is tuned to provide a persistent current and enables nociceptors to produce action potentials in response to fast-rising temperatures and thereby to protect us from heat-induced tissue damage.

Touska F, Turnquist B, Vlachova V, Reeh PW, Leffler A, Zimmermann K. Heat-resistant action potentials require TTX-resistant sodium channels NaV1.8 and NaV1.9. J Gen Physiol 150: 1125-1144, 2018.

Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW. Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447: 855-858, 2007.

The voltage-gated Kv7.2/3 channels are suprathreshold amplifiers of TRPM8-mediated cold transduction. Triggered by the activation of the menthol-receptor TRPM8 the channels are progressively closed by cold, thereby increasing the cold transduction current in the nociceptive endings of the skin. Menthol also proves to be a potent blocker of these important, pan-neuronal potassium channels and intrinsically enhances its TRPM8 agonism through this effect.

Vetter I, Hein A, Sattler S, Hessler S, Touska F, Bressan E, Parra A, Hager U, Leffler A, Boukalova S, Nissen M, Lewis RJ, Belmonte C, Alzheimer C, Huth T, Vlachova V, Reeh PW, Zimmermann K. Amplified cold transduction in native nociceptors by M-channel inhibition. The Journal of neuroscience: the official journal of the Society for Neuroscience 33: 16627-16641, 2013.

Reproduced with permission from EMBO.
(The EMBO Journal, Article "Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling" by Vetter et al, page 3795 of Volume 31, Issue 19, October 3, 2012, photo taken by Jeff Rotman)

The noxious cold transduction channel TRPA1 seems to be a central molecule in the development of pathological cold allodynia such as induced by certain fish toxins, called ciguatoxins. Ciguatoxins come from tropical dinoflagellates and accumulate in fish meat via the food chain and lead to ciguatera for which a long-lasting cold allodynia is pathognomonic. These potent sodium channel poisons causes membrane potential oscillations that lead to a sensitization of the temperature sensitivity of TRPA1 which turns temperatures that are normally pleasantly cool into the burning painful feeling of freezing cold. TRPA1 deficient mice show significantly reduced cold allodynia.

Eisenblatter A, Lewis R, Dorfler A, Forster C, Zimmermann K. Brain mechanisms of abnormal temperature perception in cold allodynia induced by ciguatoxin. Annals of neurology 81: 104-116, 2017.

Vetter I, Touska F, Hess A, Hinsbey R, Sattler S, Lampert A, Sergejeva M, Sharov A, Collins LS, Eberhardt M, Engel M, Cabot PJ, Wood JN, Vlachova V, Reeh PW, Lewis RJ, Zimmermann K. Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. The EMBO journal 31: 3795-3808, 2012.

In order to more closely research the contribution of individual ion channels to overall temperature sensitivity we developed a new scientific instrument which allows to phenotype thermal preference behavior without experimenter interference. This device allowed us to identify the contribution of TRPM8 and TRPA1 as synergistic in cold temperature perception and absence of both channels results in a much delayed cold avoidance. It can be purchased from Ugo Basile.

Winter Z, Gruschwitz P, Eger S, Touska F, Zimmermann K. Cold Temperature Encoding by Cutaneous TRPA1 and TRPM8-Carrying Fibers in the Mouse. Front Mol Neurosci 10: 209, 2017.

Touska F, Winter Z, Mueller A, Vlachova V, Larsen J, Zimmermann K. Comprehensive thermal preference phenotyping in mice using a novel automated circular gradient assay. Temperature (Austin) 3: 77-91, 2016.

Currently we aim to understand the function of cold-sensitive TRP-channels to variable cold sensitivity and how peripheral cold sensing connects with thermoregulation, metabolism and CNS processing. We are also interested in understanding the molecular pathophysiology of painful cold sensing and cold allodynia specifically with respect to individual susceptibility differences, but also in particular cold sensitive organs such as teeth.

For a list of all publications go to google scholar


Members of the Team:

Christine König
Visitenkarte
Viktor Sinica
Visitenkarte

Past Members:

PhD students:
Laura Bernal, Pamela Sotelo-Hitschfeld, Filip Touska

PostDocs:
Zoltan Winter, Aklesso Kadala, Ricardo Kusuda (FAPESP Fellow, Universidade de São Paulo, Ribeirão Preto, Brazil)

Undergraduate Students:
Aaron Tragl, Gregor Neussel, Patrick Burke, Alexander Kapp, Ziad Ahmad, Anneka Eisenblätter, Philipp Gruschwitz, Antonia Fitzek, Stefanie Eger

Collaborations:

Viktorie Vlachova, Czech Academy of Sciences, Prague, Czech Republic

Sebastian Brauchi, Universidad Austral de Chile, Valdivia, Chile

Carolina Roza, Universidad de Alcalá, Madrid, Spain

Gary Peltz, Stanford University, Palo Alto, CA, USA

Jeff Mogil, Pain Genetics, McGill University, Montreal, Canada

Simon Brookes and Rochelle Peterson, Human Physiology, Flinders University, Adelaide, Australia

Jochen Lennerz, Department of Pathology, MGH and Harvard Medical School, Boston, USA

 
Kontakt
Prof. Dr. med. Katharina Zimmermann
Telefon: 09131 85-33901
Fax: 09131 85-36903
E-Mail: katharina.zimmermann@kfa.imed.uni-erlangen.de
Visitenkarte

Mitglieder:

Christine König
PhD student

Viktor Sinica
PhD student and visiting fellow, The Czech Academy of Sciences, Prague