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Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol
Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycin...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064320/ https://www.ncbi.nlm.nih.gov/pubmed/33805979 http://dx.doi.org/10.3390/biom11040493 |
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author | Barsch, Lukas Werdehausen, Robert Leffler, Andreas Eulenburg, Volker |
author_facet | Barsch, Lukas Werdehausen, Robert Leffler, Andreas Eulenburg, Volker |
author_sort | Barsch, Lukas |
collection | PubMed |
description | Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner. |
format | Online Article Text |
id | pubmed-8064320 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80643202021-04-24 Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol Barsch, Lukas Werdehausen, Robert Leffler, Andreas Eulenburg, Volker Biomolecules Article Treating neuropathic pain remains challenging, and therefore new pharmacological strategies are urgently required. Here, the enhancement of glycinergic neurotransmission by either facilitating glycine receptors (GlyR) or inhibiting glycine transporter (GlyT) function to increase extracellular glycine concentration appears promising. Propacetamol is a N,N-diethylester of acetaminophen, a non-opioid analgesic used to treat mild pain conditions. In vivo, it is hydrolysed into N,N-diethylglycine (DEG) and acetaminophen. DEG has structural similarities to known alternative GlyT1 substrates. In this study, we analyzed possible effects of propacetamol, or its metabolite N,N-diethylglycine (DEG), on GlyRs or GlyTs function by using a two-electrode voltage clamp approach in Xenopus laevis oocytes. Our data demonstrate that, although propacetamol or acetaminophen had no effect on the function of the analysed glycine-responsive proteins, the propacetamol metabolite DEG acted as a low-affine substrate for both GlyT1 (EC50 > 7.6 mM) and GlyT2 (EC50 > 5.2 mM). It also acted as a mild positive allosteric modulator of GlyRα1 function at intermediate concentrations. Taken together, our data show that DEG influences both glycine transporter and receptor function, and therefore could facilitate glycinergic neurotransmission in a multimodal manner. MDPI 2021-03-25 /pmc/articles/PMC8064320/ /pubmed/33805979 http://dx.doi.org/10.3390/biom11040493 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ). |
spellingShingle | Article Barsch, Lukas Werdehausen, Robert Leffler, Andreas Eulenburg, Volker Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title | Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title_full | Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title_fullStr | Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title_full_unstemmed | Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title_short | Modulation of Glycinergic Neurotransmission may Contribute to the Analgesic Effects of Propacetamol |
title_sort | modulation of glycinergic neurotransmission may contribute to the analgesic effects of propacetamol |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064320/ https://www.ncbi.nlm.nih.gov/pubmed/33805979 http://dx.doi.org/10.3390/biom11040493 |
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