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Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model
The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NF...
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/PMC7957511/ https://www.ncbi.nlm.nih.gov/pubmed/33804568 http://dx.doi.org/10.3390/ijms22052479 |
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author | Mohammadzadeh, Amir Lakatos, Péter P. Balogh, Mihály Zádor, Ferenc Karádi, Dávid Árpád Zádori, Zoltán S. Király, Kornél Galambos, Anna Rita Barsi, Szilvia Riba, Pál Benyhe, Sándor Köles, László Tábi, Tamás Szökő, Éva Harsing, Laszlo G. Al-Khrasani, Mahmoud |
author_facet | Mohammadzadeh, Amir Lakatos, Péter P. Balogh, Mihály Zádor, Ferenc Karádi, Dávid Árpád Zádori, Zoltán S. Király, Kornél Galambos, Anna Rita Barsi, Szilvia Riba, Pál Benyhe, Sándor Köles, László Tábi, Tamás Szökő, Éva Harsing, Laszlo G. Al-Khrasani, Mahmoud |
author_sort | Mohammadzadeh, Amir |
collection | PubMed |
description | The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. |
format | Online Article Text |
id | pubmed-7957511 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-79575112021-03-16 Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model Mohammadzadeh, Amir Lakatos, Péter P. Balogh, Mihály Zádor, Ferenc Karádi, Dávid Árpád Zádori, Zoltán S. Király, Kornél Galambos, Anna Rita Barsi, Szilvia Riba, Pál Benyhe, Sándor Köles, László Tábi, Tamás Szökő, Éva Harsing, Laszlo G. Al-Khrasani, Mahmoud Int J Mol Sci Article The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30–60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP. MDPI 2021-03-01 /pmc/articles/PMC7957511/ /pubmed/33804568 http://dx.doi.org/10.3390/ijms22052479 Text en © 2021 by the authors. 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/). |
spellingShingle | Article Mohammadzadeh, Amir Lakatos, Péter P. Balogh, Mihály Zádor, Ferenc Karádi, Dávid Árpád Zádori, Zoltán S. Király, Kornél Galambos, Anna Rita Barsi, Szilvia Riba, Pál Benyhe, Sándor Köles, László Tábi, Tamás Szökő, Éva Harsing, Laszlo G. Al-Khrasani, Mahmoud Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title | Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title_full | Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title_fullStr | Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title_full_unstemmed | Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title_short | Pharmacological Evidence on Augmented Antiallodynia Following Systemic Co-Treatment with GlyT-1 and GlyT-2 Inhibitors in Rat Neuropathic Pain Model |
title_sort | pharmacological evidence on augmented antiallodynia following systemic co-treatment with glyt-1 and glyt-2 inhibitors in rat neuropathic pain model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957511/ https://www.ncbi.nlm.nih.gov/pubmed/33804568 http://dx.doi.org/10.3390/ijms22052479 |
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