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Control of spinal pain processing by strychnine-sensitive glycine and GABAA receptors

English title Control of spinal pain processing by strychnine-sensitive glycine and GABAA receptors
Applicant Zeilhofer Hanns Ulrich
Number 131093
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Pharmacology, Pharmacy
Start/End 01.04.2010 - 31.03.2013
Approved amount 554'488.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Neurophysiology and Brain Research

Keywords (9)

Pain; Spinal Cord; GABA; Glycine; Synaptic inhibition; Hyperalgesia; Slice; Electrophysiology; Animal model

Lay Summary (English)

Lead
Lay summary
About 20% of the general European population suffer from chronic pain. In almost two thirds of these patients, currently available pain killers (analgesic medications) provide either only unsatisfactory pain relief or cause treatment limiting side-effects. The development of novel analgesic drugs is therefore an urgent medical need. Fulfilling this need depends crucially on a better understanding of the biological basis of chronic pain. It is meanwhile generally accepted that chronic pain states are to a large extend due to an abnormal processing of pain stimuli and of other sensory stimuli in the sensory part (dorsal horn) of the spinal cord. There is increasing consensus that diminished synaptic inhibition in the spinal dorsal horn is a major contributor to chronic pain syndromes of various origins. Restoring synaptic inhibition in the spinal dorsal horn through drugs acting on the two major classes of inhibitory neurotransmitter receptors in the spinal cord, the gamma-amino butyric acid (GABA-A) receptors and strychnine-sensitive glycine receptors, should therefore be a promising strategy for the treatment of chronic pain. In the case of the GABA-A receptors we have already identified the relevant GABA-A receptor isoforms and are focussing on the site of their action within different parts of the central nervous system. While the molecular basis of drug interactions with GABA-A receptors has been carefully studied since many years, much less is known about similar possibilities at glycine receptors. We use here cannabinoid-derived molecules to identify parts of the glycine receptor molecule suitable for drug interactions. Both project parts use electrophysiological experiments in cell cultures and spinal cord slices, and behavioural testing in rodent models of chronic pain to define molecular targets for the development of novel analgesic drugs particularly useful for the treatment of chronic pain.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain
Acuña Mario, Yévenes G.E., Ralvenius W.T., Benke D., Di Lio A., Lara C.O., Muñoz B, Borgos C.F., Moraga-Cid G., Corringer P.J., Zeilhofer H.U. (2016), Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain, in Journal of Clinical Investigation, 126(7), 2547-2560.
Analgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Ralvenius William, 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.
GABAergic modulation in central sensitization in humansa randomized placebo-controlled pharmacokinetic–pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers
Besson Marie, Matthey Alain, Daali Youssef, Poncet Antoine, Vuillemier Pascal, Curatolo Michele, Zeilhofer Hanns Ulrich, Desmeules Jules (2015), GABAergic modulation in central sensitization in humansa randomized placebo-controlled pharmacokinetic–pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers, in PAIN, 156(3), 397-404.
Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla
Hofer Stefanie C., Ralvenius William T., Gachet M. Salomé, Fritschy Jean-Marc, Zeilhofer Hanns Ulrich, Gertsch Jürg (2015), Localization and production of peptide endocannabinoids in the rodent CNS and adrenal medulla, in Neuropharmacology, 98, 78-89.
Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
Paul Jolly, Yévenes Gonzalo E, Benke Dietmar, Lio Alessandra Di, Ralvenius William T, Witschi Robert, Scheurer Louis, Cook James M, Rudolph Uwe, Fritschy Jean-Marc, Zeilhofer Hanns Ulrich (2014), Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites, in Neuropsychopharmacology, 39(2), 477-487.
Antihyperalgesic effect of the GABA-A ligand clobazam in a neuropathic pain model in mice: a pharmacokinetic-pharmacodynamic study
Besson Marie, Daali Youssef, Di Lio Alessandra, Dayer Pierre, Zeilhofer Hanns Ulrich, Desmeules Jules (2013), Antihyperalgesic effect of the GABA-A ligand clobazam in a neuropathic pain model in mice: a pharmacokinetic-pharmacodynamic study, in Basic and Clinical Pharmacology and Toxicology, 112(3), 192-197.
Antihyperalgesic Effect of the GABA-A Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic-Pharmacodynamic Study
Besson Marie, Daali Youssef, Di Lio Alessandra, Dayer Pierre, Zeilhofer Hanns Ulrich, Desmeules Jules (2013), Antihyperalgesic Effect of the GABA-A Ligand Clobazam in a Neuropathic Pain Model in Mice: A Pharmacokinetic-Pharmacodynamic Study, in Basic & Clinical Pharmacology & Toxicology, 112(3), 192-197.
Genome-wide expression analysis of ptf1a- and ascl1-deficient mice reveals new markers for distinct dorsal horn interneuron populations contributing to nociceptive reflex plasticity
Wildner Hendrik, Das Gupta Rebecca, Bröhl Dominique, Heppenstall Paul A., Zeilhofer Hanns Ulrich, Birchmeier Carmen (2013), Genome-wide expression analysis of ptf1a- and ascl1-deficient mice reveals new markers for distinct dorsal horn interneuron populations contributing to nociceptive reflex plasticity, in The Journal of Neuroscience, 33(17), 7299-7307.
Chronic pain States: pharmacological strategies to restore diminished inhibitory spinal pain control.
Zeilhofer Hanns Ulrich, Benke Dietmar, Yévenes Gonzalo E (2012), Chronic pain States: pharmacological strategies to restore diminished inhibitory spinal pain control., in Annual review of pharmacology and toxicology, 52, 111-33.
Endocannabinoid-dependent plasticity at spinal nociceptor synapses
Kato Ako, Punnakkal Pradeep, Pernía-Andrade Alejandro-Javier, von Schoultz Carolin, Sharopov Salim, Nyilas Rita, Katona István, Zeilhofer Hanns Ulrich (2012), Endocannabinoid-dependent plasticity at spinal nociceptor synapses, in Journal of Physiology, 590(19), 4717-4733.
Fast synaptic inhibition in spinal sensory processing and pain control.
Zeilhofer Hanns Ulrich, Wildner Hendrik, Yévenes Gonzalo E (2012), Fast synaptic inhibition in spinal sensory processing and pain control., in Physiological reviews, 92(1), 193-235.
Selective distribution of GABA(A) receptor subtypes in mouse spinal dorsal horn neurons and primary afferents.
Paul Jolly, Zeilhofer Hanns Ulrich, Fritschy Jean-Marc (2012), Selective distribution of GABA(A) receptor subtypes in mouse spinal dorsal horn neurons and primary afferents., in The Journal of comparative neurology, 520(17), 3895-3911.
Allosteric modulation of glycine receptors.
Yévenes Gonzalo E, Zeilhofer Hanns Ulrich (2011), Allosteric modulation of glycine receptors., in British journal of pharmacology, 164(2), 224-36.
HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain.
Di Lio Alessandra, Benke Dietmar, Besson Marie, Desmeules Jules, Daali Youssef, Wang Zhi-jian, Edwankar Rahul, Cook James M, Zeilhofer Hanns Ulrich (2011), HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain., in Neuropharmacology, 60(4), 626-32.
Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids.
Yévenes Gonzalo E., Zeilhofer Hanns Ulrich (2011), Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids., in PloS one, 6(8), 23886-23886.
Presynaptic alpha2-GABA-A receptors in primary afferent depolarization and spinal pain control.
Witschi Robert, Punnakkal Pradeep, Paul Jolly, Walczak Jean-Sébastien, Cervero Fernando, Fritschy Jean-Marc, Kuner Rohini, Keist Ruth, Rudolph Uwe, Zeilhofer Hanns Ulrich (2011), Presynaptic alpha2-GABA-A receptors in primary afferent depolarization and spinal pain control., in The Journal of neuroscience, 31(22), 8134-42.
Building a Zoo of Mice for Genetic Analyses: A Comprehensive Protocol for the Rapid Generation of BAC Transgenic Mice
Johansson T, Broll I, Frenz T, Hemmers S, Becher B, Zeilhofer HU, Buch T (2010), Building a Zoo of Mice for Genetic Analyses: A Comprehensive Protocol for the Rapid Generation of BAC Transgenic Mice, in GENESIS, 48(4), 264-280.
Hoxb8-Cre Mice: A Tool for Brain-Sparing Conditional Gene Deletion
Witschi R, Johansson T, Morscher G, Scheurer L, Deschamps J, Zeilhofer HU (2010), Hoxb8-Cre Mice: A Tool for Brain-Sparing Conditional Gene Deletion, in GENESIS, 48(10), 596-602.

Collaboration

Group / person Country
Types of collaboration
McGill University Canada (North America)
- Publication
- Exchange of personnel
Neurosearch Corp Denmark (Europe)
- Industry/business/other use-inspired collaboration
AstraZeneca Canada (North America)
- Industry/business/other use-inspired collaboration
Harvard Medical School United States of America (North America)
- Publication
University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Hungarian Academy of Sciences, Institute of Experimental Medicine Hungary (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
University of Heidelberg Germany (Europe)
- Publication
University of Wisconsin Milwaukee United States of America (North America)
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Deutscher Anästhesiologiecongress Talk given at a conference Postoperative Schmerzen: Pathophysiologie – Sensibilisierungsprozesse 22.04.2013 Nürnberg, Germany, Germany Zeilhofer Hanns Ulrich;
Frontiers in Medicinal Chemistry Talk given at a conference Endocannabinoids and CB1 receptor signalling in pain 19.03.2013 Munich, Germany Zeilhofer Hanns Ulrich;
Molecular Medicine – A Neural Perspective Talk given at a conference Glycine and glycinergic neurons in spinal pain control 25.01.2013 Erlangen, Germany Zeilhofer Hanns Ulrich;
14th World Congress on Pain Talk given at a conference Glycinergic Control of Spinal Nociception – Update and Perspectives 27.08.2012 Milan, Italy Zeilhofer Hanns Ulrich;
International Symposium “Determinants and Modulators of Postoperative Pain“. Talk given at a conference Spinal pain control by GABAA receptor subtypes 21.04.2012 Erlangen, Germany, Germany Zeilhofer Hanns Ulrich;
EFIC Pain Congress 2011 Talk given at a conference Synaptic Actions of Cannabinoids in the Spinal Dorsal Horn 21.09.2011 Hamburg, Germany, Italy Zeilhofer Hanns Ulrich;
Gordon Research Conference on "Inhibition in the CNS" Talk given at a conference Presynaptic α2-GABAA receptors in primary afferent depolarization and spinal pain control 24.07.2011 Waterville, ME, USA, United States of America Zeilhofer Hanns Ulrich;
EMBO Practical Course on Mouse Phenotyping Talk given at a conference Pain phenotyping of mice 22.06.2011 Zurich, Switzerland Zeilhofer Hanns Ulrich;
Myron B. Laver Congress Talk given at a conference New Aspects of the Neurobiology of Pain 09.04.2011 Basel, Switzerland Zeilhofer Hanns Ulrich;
Annual Meeting of the Swiss Society for Neuroscience Talk given at a conference Inhibitory Interneurons in Spinal Pain Control 26.03.2011 Basel, Switzerland, Switzerland Zeilhofer Hanns Ulrich;
Gene delivery symposium Talk given at a conference Behavioral analyses of mice in pain models 17.11.2010 Stockholm, Sweden Zeilhofer Hanns Ulrich;
Biomedicum Seminars Helsinki Individual talk Spinal Neuroplasticity in Pain 01.11.2010 Helsinki, Finland, Finland Zeilhofer Hanns Ulrich;
13th World Congress on Pain Talk given at a conference Subtype-Selective GABAA Receptor Agonists in Pain 29.08.2010 Montreal, Canada, Canada Zeilhofer Hanns Ulrich;
WorldPharma 2010 (16th IUPHAR WorldCongress of Basis and Clinical Pharmacology) Talk given at a conference Targeting Disinhibition in Chronic Pain States 17.07.2010 Copenhagen, Denmark, Denmark Zeilhofer Hanns Ulrich;
7th FENS Forum of European Neuroscience Talk given at a conference Endocannabinoid Signaling in Spinal Dorsal Horn Circuits 03.07.2010 Amsterdam, Netherlands Zeilhofer Hanns Ulrich;
Cannabinoid Workshop Talk given at a conference Endocannabinoids in spinal pain processing 19.06.2010 Bonn, Germany, Germany Zeilhofer Hanns Ulrich;
1st Congress Swiss Federation of Clinical Neuro-Societies Talk given at a conference Spinal Neuroplasticity in chronic pain syndromes 03.06.2010 Basel, Switzerland Zeilhofer Hanns Ulrich;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions The (endo-)cannabinoid system in spinal pain controlling circuits. German-speaking Switzerland 2013
Talks/events/exhibitions Neurobiology of chronic pain: 1st Neurospine Meeting. Berne German-speaking Switzerland 2011
Talks/events/exhibitions Das Endocannabinoidsystem - Cannabis für das ZNS: Deutscher Schmerzkongress International 2010
Talks/events/exhibitions Pain Memory and Beyond: Animal Experimentation and Animal Wellfare at Novartis German-speaking Switzerland 2010
Talks/events/exhibitions Physiologie des Schmerzes - Gutachterkurs German-speaking Switzerland 2010

Awards

Title Year
PHOENIX Pharmazie Wissenschaftspreis - Kategorie Pharmakologie und Klinische Pharmazie 2016

Associated projects

Number Title Start Funding scheme
116064 Control of spinal pain processing by strychnine-sensitive glycine and GABAA receptors 01.04.2007 Project funding
156393 Dorsal Horn Neuronal Circuits Processing Itch 01.12.2014 Project funding

Abstract

Chronic pain constitutes a major medical and socio-economical problem worldwide. In particular chronic neuropathic pain often resists current medial treatment. It is meanwhile generally accepted that central pain sensitizing processes in the spinal cord dorsal horn are to a large extent responsible for many chronic pain syndromes. Within the last years it has become increasingly clear that a loss of spinal fast synaptic inhibition, normally provided by gamma-aminobutyric acid (GABA)ergic and glycinergic interneurons, is a key event in the generation and maintenance of pathological pain of inflammatory and neuropathic origin. A potentiation of the action of GABA and/or glycine at their dorsal horn receptors should therefore constitute a rational therapeutic strategy. We could indeed demonstrate that different forms of increased pain sensitivity can be normalized through a facilitation of spinal GABA-A receptor activation and could identify the GABA-A receptor isoforms responsible for this spinal antihyperalgesic action. Subproject A of this research proposal focuses on a better understanding of this GABA-A receptor-mediated antihyperalgesia and on the identification of strategies to restore inhibition in the sensitized spinal cord. Subproject B focuses on strychnine-sensitive glycine receptors, the other class of inhibitory neurotransmitter receptors in the spinal dorsal horn and investigates mechanisms and functional significance of their modulation by lipid signaling molecules. In subproject C, the function of a particular type of interneuron (protein kinase C-gamma positive interneurons) in the spinal dorsal horn shall be addressed through genetic ablation studies. It is believed that these neurons are critically involved in the generation of certain pain states in particular after nerve damage, yet this function has not been demonstrated directly yet. In all three subprojects an integrative approach is used with combines pharmacological, behavioral and electrophysiological experiments in genetically engineered mice.
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