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Transduction, integration, plasticity in primary nociceptive neurons
Principal Investigator: P.W. Reeh

Prof. Dr. med.
Peter W. Reeh

Dr. rer.nat.
Tatjana I. Kichko

Prof. Dr. rer.nat.
Susanne K. Sauer

Prof. Dr. med.
Michael J.M. Fischer

Dr. rer.hum.biol.
Tal Hoffmann

Dr. rer.nat
Katrin Kistner

 

Research on primary nociceptive neurons, their electrophysiological and neurochemical responses to noxious stimuli and chemical mediators. Isolated preparations and cultured dorsal root ganglion cells as well as transfected cell lines are used to study action potential discharge, ionic currents, calcium transients and release of substance P and calcitonin gene-related peptide. Aim is to elucidate nociceptive transduction and integration of stimuli as well as possible pharmacological interventions. Specific topic is sensitization by tissue acidosis and inflammatory mediators as well as their intracellular signal transduction. Transgenic mouse strains lacking different metabotropic and ionotropic receptors or thermally activated ion channels (TRPV1) are studied. Voltage-controlled ion channels (NaV, HCN) recently came in focus, because only few subtypes decide on excitability, i.e. on generation, frequency and propagation of action potentials to the central nervous system.

 

Reeh-Figure 1

 

Reeh-Fig02

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Reeh an Rosa

Wasserbad

References

Kistner K, Zimmermann K, Ehnert C, Reeh PW, Leffler A. The tetrodotoxin-resistant Na+ channel Nav1.8 reduces the potency of local anaesthetics in blocking C-fiber nociceptors. Pflügers Arch. - Europ. J. Physiol. 459 (2010) 751-763.

Auer J, Reeh PW, Fischer MJM. Acid-induced CGRP release from the stomach does not depend on TRPV1 and ASIC3. Neurogastroenterol. Motility 22 (2010) 680-687.

Finzsch M, Schreiner S, Kichko T, Reeh P, Tamm ER, Bösl MR, Meijer D, Wegner M. Sox10 is not only required for Schwann cell specification, but also for maintenance of cell identity and progression beyond the immature Schwann cell stage. J. Biol. Chem. 189 (2010) 701-712.

Fuchs D, Birklein F, Reeh PW, Sauer SK. Sensitized peripheral nociception in experimental diabetes of the rat. Pain 151 (2010) 496-505.

Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C. The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors. J Biol Chem. 285 (2010) 34781-34792.

Vellani V, Kinsey AM, Prandini M, Hechtfischer SC, Reeh P, Magherini PC, Giacomoni C, McNaughton PA. Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones. Mol Pain 6 (2010) 61-78.

Bremer M, Fröb F, Kichko T, Reeh P, Tamm ER, Suter U, Wegner M. Sox10 is required for Schwann-cell homeostasis and myelin maintenance in the adult peripheral nerve. Glia 59 (2011) 1022-1032.

Engel MA, Izydorczyk I, Mueller-Tribbensee SM, Becker C, Neurath MF, Reeh PW. Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin. Neuropeptides 45 (2011) 229-237

Engel MA, LefflerA, Niedermirtl F, Babes A, Zimmermann K, Filipovic MR, Izydorczyk I, Eberhardt M, Kichko T, Mueller-Tribbensee SM, Khalil M, Siklosi N, Nau C, Ivanovic-Burmazovic I, Neuhuber W, Becker C, Neurath MF, Reeh PW. TRPA1 and substance P mediate colitis in mice. Gastroenterology 141 (2011) 1346-1358.

Weller K, Reeh PW, Sauer SK. TRPV1, TRPA1, and CB1 in the isolated vagus nerve – axonal chemosensitivity and control of neuropeptide release. Neuropeptides 45 (2011) 391-400.

Brenneis C, Sisignano M, Coste O, Altenrath K, Fischer MJ, Angioni C, Fleming I, Brandes RP, Reeh PW, Woolf CJ, Geisslinger G, Scholich K. Soluble epoxide hydrolase limits mechanical hyperalgesia during inflammation. Mol Pain 7 (2011) 78.

Engel MA, Khalil M, Siklosi N, Mueller-Tribbensee SM, Neuhuber WL, Neurath MF, Becker C, Reeh PW. Opposite effects of substance P and calcitonin gene-related peptide in oxazolone colitis. Dig Liver Dis 44 (2012) 24-29.

Engel MA, Khalil M, Mueller-Tribbensee SM, Becker C, Neuhuber WL, Neurath MF, Reeh PW. The proximodistal aggravation of colitis depends on substance P released from TRPV1-expressing sensory neurons. J Gastroenterol. 47 (2012) 256-265.

Ditting T, Linz P, Freisinger W, Heinlein S, Reeh PW, Fiedler C, Siegel K, Scrogin KE, Neuhuber W, Veelken R. Norepinephrine reduces ω-conotoxin-sensitive Ca2+-currents in renal afferent neurons in rats. American J Physiol – Renal Physiol 302 (2011) F350-357.

Ditting T, Freisinger W, Siegel K, Fiedler C, Small L, Neuhuber W, Heinlein S, Reeh PW, Schmieder RE, Veelken R. Tonic postganglionic sympathetic inhibition induced by afferent renal nerves? Hypertension 59 (2012) 467-476.

Fröb F, Bremer M, Finzsch M, Kichko T, Reeh P, Tamm ER, Charnay P, Wegner M. Establishment of myelinating schwann cells and barrier integrity between central and peripheral nervous systems depend on Sox10. Glia 60 (2012):806-819.

Schaffler K, Reeh R, Duan R, Best AE, Othman AA, Faltynek CR, Locke C, Nothaft W. An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UVB-inflamed and normal skin. Brit. J. Clin. Pharmacol. 75 (2012) 404-414.

Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasischka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley P, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper M, Haberkorn U, Brownlee M, Reeh P, Nawroth PP. Methylglyoxal Modification of Nav1.8 Facilitates Nociceptive Neuron Firing and Causes Hyperalgesia in Diabetic Neuropathy Nat. Medicine 18 (2012) 926-933.

Sisignano M, Park C-K, Angioni C, von Hehn C, Zhang DD, Cobos E, Ghasemlou N, Xu Z-Z, Kumaran V, Lu R, Grant A, Fischer M, Schmidtko A, Reeh P, Ji R-R, Woolf C, Geisslinger G, Scholich K, Brenneis C. 5,6-EET is released upon neuronal activity and induces mechanical pain hypersensitivity via TRPA1 on central afferent terminals. J Neurosci. 32 (2012) 6364-6372.

Leffler A, Frank G, Kistner K, Niedermirtl F, Koppert W, Reeh PW, Nau C. Local Anesthetic-like Inhibition of Voltage Gated Na+ Channels by the Partial µ-Opioid Receptor Agonist Buprenorphine. Anesthesiology 116 (2012) 1335-1346.

Hackel D, Krug SM, Sauer RS, Mousa SA, Böcker A, Pflücke D, Wrede EJ, Kistner K, Hoffmann T, Niedermirtl B, Sommer C, Bloch L, Huber O, Blasig IE, Amasheh S, Reeh PW, Fromm M, Brack A, Rittner HL. Transient opening of the perineural barrier for analgesic drug delivery. Proc. Natl. Acad. Sci. USA 109 (2012) E2018-2027.

Eberhardt MJ, Filipovic MR, Leffler A, de la Roche J, Kistner K, Fischer MJ, Fleming T, Zimmermann K, Ivanovic-Burmazovic I, Nawroth PP, Bierhaus A, Reeh PW, Sauer SK. Methylglyoxal activates nociceptors through TRPA1 – a possible mechanism of metabolic neuropathies. J. Biol. Chem. 287 (2012) 28291-28306.

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, Vlachová V, Reeh PW, Lewis RJ, Zimmermann K. Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. EMBO J. 31 (2012) 3795-3808.

Brenneis C, Kistner K, Puopolo M, Segal D, Sisignana M, Labocha S, Ferreiros N, Strominger A, Cobos EJ, Ghasemlou N, Geisslinger G, Reeh P, Bean BP, Woolf CJ. Phenotyping the function of TRPV1-expressing sensory neurons by targeted axonal silencing. J. Neurosci. 33 (2013) 315-326.

Brenneis C, Kistner K, Puopolo M, Jo S, Segal D, Sisignano M, Cobos del Moral E, Wainger E, Labocha S, Ferreirós N, von Hehn C, Geisslinger G, Reeh P, Bean BP, Woolf CJ. Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block. Brit. J. Pharmacol. (2013) in press.

Filipovic M, Eberhardt M, Prokopovic V, Mijuskovic A, Orescanin-Dusic Z, Reeh P, Ivanovic-Burmazovic I. Beyond H2S and NO interplay: hydrogen sulfide and nitroprusside react directly to give nitroxyl (HNO). A new pharmacological source of HNO. J. Med. Chem. 56 (2013) 1499-1508.

Babes A, Fischer MJ, Filipovic M, Engel MA, Flonta ML, Reeh PW: The anti-diabetic drug glibenclamide is an agonist of the transient receptor potential Ankyrin 1 (TRPA1) ion channel. Eur J Pharmacol, 704 (2013) 15-22.

Hoffmann T, Kistner K, Miermeister F, Winkelmann R, Wittmann J, Fischer MJ, Weidner C, Reeh PW. TRPA1 and TRPV1 are differentially involved in heat nociception of mice. Eur J Pain. 17 (2013) 1472-1482.

de la Roche J, Eberhardt MJ, Klinger AB, Stanslowsky N, Wegner F, Koppert W, Reeh PW, Lampert A, Fischer MJM, Leffler A. The molecular basis of species-specific activation of human TRPA1 by protons involves poorly conserved residues within transmembrane domains 5 and 6. J. Biol.Chem.  288(2013) 20280-20292.

Zimmermann K, Deuis JR, Inserra MC, Collins LS, Namer B, Cabot PJ, Reeh PW, Lewis RJ, Vetter I. Analgesic treatment of ciguatoxin-induced cold allodynia. Pain 154 (2013) 1999-2006.

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. J Neurosci. 33 (2013) 16627-16641.

Kichko TI, Lennerz J, Eberhardt M, Babes RM, Neuhuber W, Kobal G, Reeh PW. Bimodal concentration-response of nicotine involves the nicotinic acetylcholine receptor, transient receptor potential vanilloid type 1, and transient receptor potential ankyrin 1 channels in mouse trachea and sensory neurons. J Pharmacol Exp Ther. 347 (2013) 529-539.

Fischer M, Carli G, Raboisson P, Reeh P. The interphase of the formalin test. Pain (2013) in press.

Eberhardt M, Dux M, Namer B, Cordasic N, Miljkovic J, de la Roche J, Fischer M, Leffler A, Babes A, Lampert A, Jacobi J, Messlinger K, Ivanovic-Burmazovic I, Reeh P, Filipovic MR. Nitroxyl (HNO), a product of H2S and NO interaction, activates the TRPA1-CGRP pathway as a route to systemic neurovascular effects. Nature Neuroscience (2013) submitted.