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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

Authors :
Amir Mohammadzadeh
Péter P. Lakatos
Mihály Balogh
Ferenc Zádor
Dávid Árpád Karádi
Zoltán S. Zádori
Kornél Király
Anna Rita Galambos
Szilvia Barsi
Pál Riba
Sándor Benyhe
László Köles
Tamás Tábi
Éva Szökő
Laszlo G. Harsing
Mahmoud Al-Khrasani
Source :
International Journal of Molecular Sciences, Vol 22, Iss 5, p 2479 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
14220067 and 16616596
Volume :
22
Issue :
5
Database :
Directory of Open Access Journals
Journal :
International Journal of Molecular Sciences
Publication Type :
Academic Journal
Accession number :
edsdoj.78ce24478dcd4e6eb0152d1b4bcae416
Document Type :
article
Full Text :
https://doi.org/10.3390/ijms22052479