In addition to patient care and clinical research, experimental research represents the third field of activity of the Department of Anesthesiology and Surgical Intensive Care Medicine. In our research laboratory we work on translational and basic scientific topics in the field of pain and inhibitory neurotransmission, especially glycinergic neurotransmission. The aim is to identify novel therapeutic approaches for the treatment and/or prevention of chronic pain.
The perception of pain represents an important warning function of the body and protects it from potential damage. Chronic inflammation, systemic disease, or lesions in the peripheral or central nervous system can lead to pathological nociceptive hyperactivity. This manifests as a spontaneous and/or excessive pain response to non-painful or mild stimuli (allodynia or hyperalgesia). Despite intensive research, these chronic forms of pain have been difficult to treat. In a significant proportion of patients, treatment success is unsatisfactory, partly due to serious side effects of the drugs used, partly due to insufficient efficacy of the respective therapies. Extensive data suggest that the chronification of pain causes neuroplastic changes within the central nervous system that lead to specific differences in the processing of chronic and acute pain. It is known that, particularly in the dorsal horn of the spinal cord, the balance of synaptic excitation and inhibition changes during the development of chronic pain, and this is likely to contributes to the pathogenesis of chronic pain. In particular, changes in glycinergic inhibition have only superficially studied and pharmacological interventions have so far been impossible or poorly feasible due to the poorly developed pharmacology of glycinergic neurotransmission.
In this project, we use multidisciplinary approaches to try to understand the mechanisms underlying neuroplastic changes involved in the establishment of chronic pain and develop novel therapeutic concepts based on them.
As a novel approach for the treatment of chronic pain, we are investigating the possibilities of enhancing glycinergic inhibition indirectly by inhibition through glycine transporters (GlyT). We are investigating the mechanisms of action of these substances and the functions of these transporters in in vitro and in vivo, using biochemical, pharmacological, electrophysiological, and mouse genetic methods.
Armbruster A, Neumann E, Kötter V, Hermanns H, Werdehausen R and Eulenburg V (2018) The GlyT1 Inhibitor Bitopertin Ameliorates Allodynia and Hyperalgesia in Animal Models of Neuropathic and Inflammatory Pain. Front. Mol. Neurosci. 10:438. doi: 10.3389/fnmol.2017.00438.
Barsch, L, Werdehausen R, Leffler A, and Eulenburg V (2022) Modulation of Glycinergic Neurotransmission May Contribute to the Analgesic Effects of Propacetamol“. Biomolecules. 11:493. doi.org/10.3390/biom11040493.
Groemer, Teja Wolfgang, Antoine Triller, Hanns Ulrich Zeilhofer, Kristina Becker, Volker Eulenburg, und Cord Michael Becker (2022) Nociception in the Glycine Receptor Deficient Mutant Mouse Spastic. Frontiers in mol. Neurosci 15: 83249 doi.org/10.3389/fnmol.2022.832490.
Kurolap A*, Armbruster A*, Hershkovitz T, Hauf K, Mory A, Paperna T, Hannappel E, Tal G, Nijem Y, Sella E, Mahajnah M, Ilivitzki A, Hershkovitz D, Ekhilevitch N, Mandel H, Eulenburg V$*, Baris H$* (2016) Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine. Am J Hum Gen 99: 1172-1180 doi: 10.1016/j.ajhg.2016.09.004.
Werdehausen R, Mittnacht S, Bee LA, Minett MS, Armbruster A, Bauer I, Wood JN, Hermanns H, Eulenburg V (2015) The lidocaine metabolite N-ethylglycine has antinociceptive effects in experimental inflammatory and neuropathic pain. Pain, 156, 1647-59.
TRANSPORTER-DEPENDENT REGULATION OF GLYCINERGIC NEURTRANSMISSION
Glycine is an important inhibitory neurotransmitter, but additionally functions as an essential coagonist at excitatory glutamate receptors of the N-methyl-D-aspartate (NMDAR) subtype. Regulation of extracellular glycine concentration at both synapse types occurs via glycine transport systems with high affinity and capacity that catalyze the transport of glycine across the membranes of presynaptic terminals and glial cells surrounding the synapse, respectively. Although most cells at glycine-dependent synapses express more than one transporter with high affinity for glycine, their precise function as well as their functional interaction is poorly understood. In this project, we investigate how transporters with high affinity for glycine, which are the mainly astroglially expressed glycine transporter 1 (GlyT1; SLC6A9), the both neuronally and astoglially expressed the alanine-serine-cysteine-1 transporter (ASC-1, SLC7A10), and the exclusively neuronally expressed GlyT2 (Slc6a5) interact with each other in maintaining glycine homeostasis at glycinergic synapses, and how their function changes during development.
The goal of this project is to clarify the individual contribution of glycine-specific transporters to the regulation of glycine-dependent neurotransmission. Here, we will elucidate the functions of each transporter at inhibitory synapses in order to clarify the precise mechanisms of how these transporters interact with each other for the maintenance of the glycine circuit at glycinergic synapses. We plan to undertake this project using an interdisciplinary approach that employs complex genetic and RNAi techniques in addition to biochemical and electrophysiological methods.
Eulenburg V, and Hülsmann S (2022) Synergistic Control of Transmitter Turnover at Glycinergic Synapses by GlyT1, GlyT2, and ASC-1“ Int. J. Med. Sci. 23:2561 doi.org/10.3390/ijms23052561.
Hauf, K., Barsch L, Bauer D, Buchert R, Armbruster A, Frauenfeld L, Grasshoff U, and V. Eulenburg. (2020) GlyT1 Encephalopathy: Characterization of Presumably Disease Causing GlyT1 Mutations. Neuroichem. Int. 139: 104813. doi.org/10.1016/j.neuint.2020.104813.
Hirrlinger J, Marx G, Besser S, Sicker M, Köhler S, Hirrlinger PG, Wojcik SM, Eulenburg V, Winkler U, Hülsmann S. (2019) GABA-Glycine Cotransmitting Neurons in the Ventrolateral Medulla: Development and Functional Relevance for Breathing Front. Cell. Neurosci 13: 517 doi.org/10.3389/fncel.2019.00517.
Eulenburg V, Knop G, Sedmak S, Schuster S, Hauf K, Schneider J, Feigenspan A, Joachimsthaler A, and Brandstätter JH. (2018) GlyT1 Determines the Glycinergic Phenotype of Amacrine Cells in the Mouse Retina. Brain Struct. Funct. 223: 3251-66 doi.org/10.1007/s00429-018-1684-3.
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