Glycine Transporter 1 Inhibitors Minimize the Analgesic Tolerance to Morphine.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Morphine*/pharmacology ; Glycine Plasma Membrane Transport Proteins*/antagonists & inhibitors ; Glycine Plasma Membrane Transport Proteins*/metabolism ; Drug Tolerance* ; Analgesics, Opioid*/pharmacology ; Receptors, N-Methyl-D-Aspartate*/metabolism ; Receptors, N-Methyl-D-Aspartate*/antagonists & inhibitors; Animals ; Rats ; Male ; Glycine/analogs & derivatives ; Glycine/pharmacology ; Rats, Sprague-Dawley ; Glutamic Acid/metabolism

Opioid analgesic tolerance (OAT), among other central side effects, limits opioids' indispensable clinical use for managing chronic pain. Therefore, there is an existing unmet medical need to prevent OAT. Extrasynaptic N-methyl D-aspartate receptors (NMDARs) containing GluN2B subunit blockers delay OAT, indicating the involvement of glutamate in OAT. Glycine acts as a co-agonist on NMDARs, and glycine transporters (GlyTs), particularly GlyT-1 inhibitors, could affect the NMDAR pathways related to OAT. Chronic subcutaneous treatments with morphine and NFPS, a GlyT-1 inhibitor, reduced morphine antinociceptive tolerance (MAT) in the rat tail-flick assay, a thermal pain model. In spinal tissues of rats treated with a morphine-NFPS combination, NFPS alone, or vehicle-comparable changes in µ-opioid receptor activation, protein and mRNA expressions were seen. Yet, no changes were observed in GluN2B mRNA levels. An increase was observed in glycine and glutamate contents of cerebrospinal fluids from animals treated with a morphine-NFPS combination and morphine, respectively. Finally, GlyT-1 inhibitors are likely to delay MAT by mechanisms relying on NMDARs functioning rather than an increase in opioid efficacy. This study, to the best of our knowledge, shows for the first time the impact of GlyT-1 inhibitors on MAT. Nevertheless, future studies are required to decipher the exact mechanisms.

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FK_138389 Ministry of Innovation and Technology of Hungary from the Na-tional Research, Development and Innovation Fund; TKP 2021 EGA-25 Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology Thematic Programme of Semmelweis University

Keywords: NFPS; NMDARs; glycine transporter-1; opioid analgesic tolerance

76I7G6D29C (Morphine)
0 (Glycine Plasma Membrane Transport Proteins)
0 (Analgesics, Opioid)
0 (Receptors, N-Methyl-D-Aspartate)
TE7660XO1C (Glycine)
3KX376GY7L (Glutamic Acid)
0 (NR2B NMDA receptor)

Date Created: 20241026 Date Completed: 20241026 Latest Revision: 20241104

20241105

PMC11508341

10.3390/ijms252011136

39456918