Pain; Spinal Cord; GABA; Glycine; Synaptic inhibition; Hyperalgesia; Slice; Electrophysiology; Animal model
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Yévenes Gonzalo E, Zeilhofer Hanns Ulrich (2011), Allosteric modulation of glycine receptors., in British journal of pharmacology
, 164(2), 224-36.
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.
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.
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.
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.
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.
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.