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Dorsal Horn Neuronal Circuits Processing Itch

English title Dorsal Horn Neuronal Circuits Processing Itch
Applicant Zeilhofer Hanns Ulrich
Number 156393
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.12.2014 - 30.11.2017
Approved amount 947'427.90
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Keywords (3)

Synaptic inhibition; Neuronal circuit; Itch

Lay Summary (German)

Lead
Chronischer Juckreiz ist eine häufige, sehr beeinträchtigende und nur schwer behandelbare Erkrankung. In den letzten Jahren wurden Entdeckungen gemacht, die es jetzt ermöglichen die neurophysiologischen Grundlagen des Juckreizes besser zu verstehen. Ähnlich wie Schmerzsignale wird auch Juckreiz zunächst von einem Netzwerk von Nervenzellen im Rückenmark verarbeitet. Unser Projekt zielt darauf, die an dieser Verarbeitung beteiligten Nervenzellen, Ihre Verschaltung, Kommunikation und die Regulation ihrer Aktivität besser verstehen zu können, um dieses Wissen später zur Therapie von Patienten ausnutzen zu können.
Lay summary
Wir verwenden molekularbiologische Methoden und Gewebefärbungen, um die an der Juckreizverarbeitung beteiligten Neuronen zu identifizieren. In Gewebeschnitten und in narkotisierten Mäusen führen wir bildgebende und elektrische Messungen durch, um zu untersuchen, durch welche Botenstoffe und Rezeptoren die Aktivität dieser Zellen reguliert wird. Der mögliche therapeutische Nutzen dieser Ergebnisse wird dann in pharmakogenetischen und pharmakologischen Experimenten überprüft. Wir erhoffen uns von diesem Projekt nicht nur ein besseres Verständnis der neurophysiologischen Grundlagen der Juckreizverarbeitung, sondern hoffen auch die Grundlagen für neue therapeutische Ansätze zu legen.
Direct link to Lay Summary Last update: 28.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Flexible and Lightweight Devices for Wireless Multi-Color Optogenetic Experiments Controllable via Commercial Cell Phones
Mayer Philipp, Sivakumar Nandhini, Pritz Michael, Varga Matjia, Mehmann Andreas, Lee Seunghyun, Salvatore Alfredo, Magno Michele, Pharr Matt, Johannssen Helge C., Troester Gerhard, Zeilhofer Hanns Ulrich, Salvatore Giovanni Antonio (2019), Flexible and Lightweight Devices for Wireless Multi-Color Optogenetic Experiments Controllable via Commercial Cell Phones, in Frontiers in Neuroscience, 13, 1-14.
How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch
Pagani Martina, Albisetti Gioele W., Sivakumar Nandhini, Wildner Hendrik, Santello Mirko, Johannssen Helge C., Zeilhofer Hanns Ulrich (2019), How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch, in Neuron, 103(1), 102-117.e5.
Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals
Albisetti Gioele W., Pagani Martina, Platonova Evgenia, Hösli Ladina, Johannssen Helge C., Fritschy Jean-Marc, Wildner Hendrik, Zeilhofer Hanns Ulrich (2019), Dorsal Horn Gastrin-Releasing Peptide Expressing Neurons Transmit Spinal Itch But Not Pain Signals, in The Journal of Neuroscience, 39(12), 2238-2250.
Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors
Ralvenius William T., Neumann Elena, Pagani Martina, Acuña Mario A., Wildner Hendrik, Benke Dietmar, Fischer Nina, Rostaher Ana, Schwager Simon, Detmar Michael, Frauenknecht Katrin, Aguzzi Adriano, Hubbs Jed Lee, Rudolph Uwe, Favrot Claude, Zeilhofer Hanns Ulrich (2018), Itch suppression in mice and dogs by modulation of spinal α2 and α3GABAA receptors, in Nature Communications, 9(1), 3230-3230.
TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABAA receptors
Neumann Elena, Ralvenius William T., Acuña Mario A., Rudolph Uwe, Zeilhofer Hanns Ulrich (2018), TP003 is a non-selective benzodiazepine site agonist that induces anxiolysis via α2GABAA receptors, in Neuropharmacology, 143, 71-78.
Circuit dissection of the role of somatostatin in itch and pain
Huang Jing, Polgár Erika, Solinski Hans Jürgen, Mishra Santosh K., Tseng Pang-Yen, Iwagaki Noboru, Boyle Kieran A., Dickie Allen C., Kriegbaum Mette C., Wildner Hendrik, Zeilhofer Hanns Ulrich, Watanabe Masahiko, Riddell John S., Todd Andrew J., Hoon Mark A. (2018), Circuit dissection of the role of somatostatin in itch and pain, in Nature Neuroscience, 21(5), 707-716.
Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus.
Albisetti Gioele W, Ghanem Alexander, Foster Edmund, Conzelmann Karl-Klaus, Zeilhofer Hanns Ulrich, Wildner Hendrik (2017), Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 37(43), 10358-10371.
Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters.
Haenraets Karen, Foster Edmund, Johannssen Helge, Kandra Vinnie, Frezel Noémie, Steffen Timothy, Jaramillo Valeria, Paterna Jean-Charles, Zeilhofer Hanns Ulrich, Wildner Hendrik (2017), Spinal nociceptive circuit analysis with recombinant adeno-associated viruses: the impact of serotypes and promoters., in Journal of neurochemistry, 142(5), 721-733.
Glycine receptors and glycine transporters: targets for novel analgesics?
Zeilhofer Hanns Ulrich, Acuña Mario A, Gingras Jacinthe, Yévenes Gonzalo E (2017), Glycine receptors and glycine transporters: targets for novel analgesics?, in Cellular and molecular life sciences : CMLS.
GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET.
Müller Herde Adrienne, Benke Dietmar, Ralvenius William T, Mu Linjing, Schibli Roger, Zeilhofer Hanns Ulrich, Krämer Stefanie D (2017), GABAA receptor subtypes in the mouse brain: Regional mapping and diazepam receptor occupancy by in vivo [18F]flumazenil PET., in NeuroImage, 150, 279-291.
The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia.
Ralvenius William T, Acuña Mario A, Benke Dietmar, Matthey Alain, Daali Youssef, Rudolph Uwe, Desmeules Jules, Zeilhofer Hanns Ulrich, Besson Marie (2016), The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia., in Neuropharmacology, 109(10), 366-375.
Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain.
Acuña Mario A, Yévenes Gonzalo E, Ralvenius William T, Benke Dietmar, Di Lio Alessandra, Lara Cesar O, Muñoz Braulio, Burgos Carlos F, Moraga-Cid Gustavo, Corringer Pierre-Jean, Zeilhofer Hanns Ulrich (2016), Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain., in The Journal of clinical investigation, 126(7), 2547-60.
Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics.
Zeilhofer Hanns Ulrich, Ralvenius William T, Acuña Mario A (2015), Restoring the spinal pain gate: GABA(A) receptors as targets for novel analgesics., in Advances in pharmacology (San Diego, Calif.), 73, 71-96.
Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype.
Ralvenius William T, Benke Dietmar, Acuña Mario A, Rudolph Uwe, Zeilhofer Hanns Ulrich (2015), Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype., in Nature communications, 6, 6803.
Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch.
Foster Edmund, Wildner Hendrik, Tudeau Laetitia, Haueter Sabine, Ralvenius William T, Jegen Monika, Johannssen Helge, Hösli Ladina, Haenraets Karen, Ghanem Alexander, Conzelmann Karl-Klaus, Bösl Michael, Zeilhofer Hanns Ulrich (2015), Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch., in Neuron, 85(6), 1289-304.

Collaboration

Group / person Country
Types of collaboration
David Bennett / University of Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Uwe Rudolph / Harvard Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Andrew J Todd / University of Glasgow Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Bruno Weber / University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Xinzhong Dong / Johns Hopkins University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Neurocycle Therapeutics United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Industry/business/other use-inspired collaboration

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting of the Society for Neuroscience Poster Gastrin releasing peptide boosts the functional output from spinal itch-processing circuits 12.11.2017 Washington, DC, United States of America Pagani Martina;
Annual Meeting of the Society for Neuroscience Poster Gastrin releasing peptide neurons in itch processing circuits of the spinal cord 03.11.2017 Washingon, DC, United States of America Albisetti Gioele;
9th World Congress on Itch Talk given at a conference Spinal GABAA receptor subtypes controlling itch 15.10.2017 Breslau, Poland Zeilhofer Hanns Ulrich;
9th World Congress on itch Poster Spinal release of gastrin releasing peptide (GRP) is required for suprathreshold synaptic activation of GRP receptor (GRPR)-positive neurons talk 01.10.2017 Breslau, Poland Pagani Martina;
Molecular Basis of Life 2017. International Fall Meeting of the Gesellschaft für Biochemie und Molekularbiologie (GMB). Talk given at a conference Restoring the spinal pain gate: subtype-specific GABA-A receptor ligands against chronic pain. 25.09.2017 Bochum, Germany Zeilhofer Hanns Ulrich;
Pain in Europe X Talk given at a conference What’s going on at the gate? 05.09.2017 Copenhagen, Denmark Zeilhofer Hanns Ulrich;
Jerusalem Brain Community. Israel Institute of Advanced Studies. Talk given at a conference GABA and pain: from gate control to restoring inhibition 03.05.2017 Jerusalem, Israel Zeilhofer Hanns Ulrich;
Leopoldina Symposium. Evolution of intensive care. Talk given at a conference GABAA receptors – forgotten targets? 24.02.2017 Berlin, Germany Zeilhofer Hanns Ulrich;
Symposium Experimental Pharmacology, LS2 Meeting Talk given at a conference New approaches to chronic pain 02.02.2017 Zurich, Switzerland Zeilhofer Hanns Ulrich;
Annual Meeting of the Swiss Society for Neuroscience Poster GRP neurons in itch processing circuits of the spinal cord 27.01.2017 Basel, Switzerland Albisetti Gioele;
Annual Meeting of the Society for Neuroscience Poster Acute and chronic itch are suppressed by positive allosteric modulators of α2- and α3-GABAA receptors 12.11.2016 San Diego, United States of America Ralvenius William;
3rd SFCNS (Swiss Federation of Clinical Neuro-Societies) Congress Talk given at a conference Spinal Pain Processing 30.09.2016 Basel, Switzerland Zeilhofer Hanns Ulrich;
Pain Mechanisms and Therapeutics Conference Talk given at a conference Glycinergic dorsal horn neurons in spinal control of pain and itch 04.06.2016 Taormina, Italy Zeilhofer Hanns Ulrich;
16th Conference of the International Society for Monitoring Molecules in Neuroscience Talk given at a conference Glycinergic neurons of the spinal dorsal horn in pain and itch 31.05.2016 Göteburg, Sweden Zeilhofer Hanns Ulrich;
Allosteric Modulation of Inhibitory Ion Channel Function: Concepts and New Therapeutic Opportunities Talk given at a conference German Pharm-Tox Summit. Annual Meeting of the German Society for Pharmacology and Toxocology 03.03.2016 Berlin, Germany Zeilhofer Hanns Ulrich;
Departmental Seminar. Instituto de Neurociencias, Alicante Individual talk Dissecting the Functions of Inhibitory Dorsal Horn Neurons 26.02.2016 Alicante, Spain Zeilhofer Hanns Ulrich;
Departmental Seminar. Institut de Biologie du Dévelopement de Marseille (IBDM). Individual talk Dissecting inhibitory dorsal horn neuron functions. 04.11.2015 Marseille, France Zeilhofer Hanns Ulrich;
Seminar University of Pittsburgh Individual talk Dissecting the functions of dorsal horn interneurons through intersectional gene targeting. 22.10.2015 Pittsburgh, United States of America Zeilhofer Hanns Ulrich;
Gordon Research Conference: Inhibition in the CNS Talk given at a conference GABAA Receptors and Spinal Pain Control 16.08.2015 Lewiston, United States of America Zeilhofer Hanns Ulrich;
9th Conference on the Mechanisms of Anaesthesia Talk given at a conference GABAA receptors as analgesic drug targets 16.06.2015 Bonn, Germany Zeilhofer Hanns Ulrich;
The Challenge of Chronic Pain Talk given at a conference Behavioral consequences of targeted ablation, silencing and activation of glycinergic dorsal horn neurons for pain and itch 11.03.2015 Cambridge, Great Britain and Northern Ireland Zeilhofer Hanns Ulrich;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Glycine and GABAA Receptors Controlling the Spinal Relay of Pain and Itch Talk 10.11.2017 Cambridge, MA, United States of America Zeilhofer Hanns Ulrich;
Analgetika – Ein Update Talk 20.05.2015 Zurich, Switzerland Zeilhofer Hanns Ulrich;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Schmerz: Alarm und Fehlalarm in unserem Körper German-speaking Switzerland 2016
Media relations: print media, online media Spinal cord neurons that control pain and itch ETH Website International 2015
Media relations: print media, online media Spinal cord neurons that control pain and itch UZH Website International 2015

Awards

Title Year
Phoenix Pharmacy Scientific Prize, Category Pharmacology and Clinical Pharmacy 2016

Associated projects

Number Title Start Funding scheme
131093 Control of spinal pain processing by strychnine-sensitive glycine and GABAA receptors 01.04.2010 Project funding
170804 The airy scan detector for improved sensitivity and resolution analysis of functional neuroanatomy, neuronal regulation, and pericyte biology 01.04.2017 R'EQUIP
176398 Dorsal Horn Neuronal Circuits Processing Itch 01.12.2017 Project funding
176398 Dorsal Horn Neuronal Circuits Processing Itch 01.12.2017 Project funding

Abstract

Besides pain, itch is a second sensation that has evolved to protect higher organisms from potential environmental harm. Under physiological conditions, both sensations originate from the activation of plasma membrane receptors on primary afferent sensory neurons that convey these signals to the spinal cord and brainstem. During the last decade, several receptors have been identified which are specifically activated by pruritic (itch-inducing) stimuli. Less is known about downstream dorsal horn circuits and the spinal processing of itch-related signals. Two neuropeptides, gastrin releasing peptide (GRP) and b-type natriuretic peptide (BNP) have been considered as spinal messengers of itch. The present proposal addresses a dorsal horn neuronal circuit involved in itch processing and its control by inhibitory interneurons and itch-related neuropeptides. The starting point of these studies will be GRP expressing dorsal horn neurons, which are critical for the spinal relay of some forms of itch. Diphtheria toxin-mediated ablation of these neurons reduced chloroquine-induced itch responses in behaving mice. Additional preliminary data from rabies virus-based retrograde tracing experiments indicate that the majority of spinal interneurons presynaptic to GRP neurons are inhibitory (presumably combined GABA/glycinergic) interneurons of the deep dorsal horn. Here, we propose to use rabies virus-based retrograde tracing experiments, targeted electrophysiological recordings in spinal cord slices in combination with optogenetics, in vivo 2-photon recordings, and behavioural tests to elucidate an itch-related dorsal horn neuronal circuit and its control by inhibitory interneurons. From these experiments, we expect to gain novel insights into the spinal processing of this still poorly understood sense.
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