PhD Scientific Days 2023

Budapest, 22-23 June 2023

Pharmaceutical Sciences - Posters E

Glycine transporter-1 Inhibitors delay the development of morphine antinociceptive tolerance in rats

Anna Rita Galambos1, Nariman Essmat1, Péter Pál Lakatos2, Sarah Kadhim Abbood1, Orsolya Geda2, Pál Riba1, Kornél Király1, Éva Szökő2, László Gábor Harsing1, Tamás Tábi2, Ferenc Zádor3, Mahmoud Al Khrasani1

1Department of Pharmacology and Pharmacotherapy, Semmelweis University, 4 Nagyvárad tér, Budapest, H-1089, Hungary.
2Department of Pharmacodynamics, Semmelweis University, 4 Nagyvárad tér, Budapest, H-1089, Hungary.
3Pharmacological and Drug Safety Research, Gedeon Richter Plc, Budapest, Hungary

Text of the abstract

INTRODUCTION: Opioid analgesics are a mainstay in the management of mild-severe pain, however their long-term use is limited by development of analgesic tolerance. Recent data reveal that glycine transporter-1 (GlyT-1) inhibitors could halt neuropathic pain which share overlapping spinal mechanisms with opioid tolerance.
AIMS: To elucidate the impact of GlyT-1 inhibitors on opioid antinociceptive tolerance developed following repeated morphine administration.
METHODS: Thermal pain model, the rat tail-flick assay was used. Male Wistar rats (180-250g) were treated with subcutaneous morphine alone or in combination with NFPS, GlyT-1 inhibitor. The pain threshold was determine prior to and 30, 60, 120, 180 min after treatment with morphine (10mg/kg), NFPS (0.3 and 0.6mg/kg), combination and vehicle at day 1 and 10. In addition, cerebrospinal fluid (CSF) was collected from treated animals at the end of the treatment period, and glycine levels were measured by capillary electrophoresis. Rat motor function was also measured by the rotarod test on the 1st and 10th day. Area under curve values of the antinociceptive time-effect course were obtained from individual animals. To determine the statistical significance, One-way ANOVA followed by Newman-Keuls multiple comparison test was used.
RESULTS: Acute treatment with systemic 10 mg/kg morphine produced significant antinociceptive effects, however, following 10 days treatments the antinociceptive effect was largely decreased indicating the development of morphine antinociceptive tolerance. NFPS similar to vehicle failed to show antinociception either after acute or chronic treatment. NFPS showed no impact on the acute effect of morphine. On the other hand, chronic treatment with 0.6 mg/kg NFPS significantly ameliorated the morphine tolerance. Chronic treatment with 0.3 mg/kg NFPS failed to affect the motor function of the animals at the tested time points. In capillary electrophoresis study, NFPS in test dose and in combination with morphine compared to vehicle increased CSF glyine level.
CONCLUSIONS: GlyT-1 inhibitors are a novel tool to delay the development of morphine antinociceptive tolerance, by augmenting the spinal glycinergic system either through activation of glycinergic receptors at post-synaptic or on glial cells which is implicated in opioid tolerance.
FUNDING: FK-138389, SE 250+ Kiválósági PhD Ösztöndíj