Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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
_version_ 1783664665303187456
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
work_keys_str_mv AT mohammadzadehamir pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT lakatospeterp pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT baloghmihaly pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT zadorferenc pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT karadidavidarpad pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT zadorizoltans pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT kiralykornel pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT galambosannarita pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT barsiszilvia pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT ribapal pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT benyhesandor pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT koleslaszlo pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT tabitamas pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT szokoeva pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT harsinglaszlog pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel
AT alkhrasanimahmoud pharmacologicalevidenceonaugmentedantiallodyniafollowingsystemiccotreatmentwithglyt1andglyt2inhibitorsinratneuropathicpainmodel