PhD Scientific Days 2024

Budapest, 9-10 July 2024

Poster Session D - Neurosciences 1.

Glycine Transporter 1 Inhibitors Delay Morphine Analgesic Tolerance In Rats


Galambos Anna1, Lakatos Péter P.2, Zádor Ferenc1,3, Tábi Tamás2, Ifj. Hársing G. László1, Al-Khrasani Mahmoud1
1: SE Department of Pharmacology and Pharmacotherapy
2: SE Department of Pharmacodinamics
3: Pharmacological and Drug Safety Research, Gedeon Richter Plc

Text of the abstract

Introduction: Opioid analgesics are a mainstay in the management of mild to severe acute and chronic pain, yet their long term-application is limited by side effects. The majority of current prescribed opioid analgesics target μ-opioid receptors (MORs). Long-term use of MOR agonists develops analgesic tolerance, dose escalation is required to retain the opioid analgesic efficacy, increasing the side effects too. Despite numerous efforts being done to delay tolerance development, none of them have clinical relevance. Thus, exploring new treatment avenues is crucial for chronic pain patients. Recent research suggests that glycine transporter-1 (GlyT1) inhibitors have potential in halting neuropathic pain, which shares certain spinal mechanisms with opioid tolerance such as iNMDARs' activation.
Aims: To investigate the involvement of the spinal glycinergic system in morphine analgesic tolerance development and to assess the impact of the selective GlyT1 inhibitor NFPS on opioid antinociceptive tolerance following repeated morphine administration.
Methods: In vivo and in vitro studies were applied to measure tolerance and NFPS effect. The rat tail-flick assay, a thermal pain model was employed, where male Wistar rats (170-230g) received sc. morphine, NFPS or their combination for 10 days. Pain threshold was measured before and after treatment. After 10 day-treatment, cerebrospinal fluid (CSF) glycine levels were measured using capillary electrophoresis. Motor function was assessed by the rotarod test. Statistical analysis was performed using appropriate tests.
Results: Acute morphine treatment (10 mg/kg) resulted in significant antinociceptive effects, but high degree of tolerance was measured after 10 days. NFPS failed to show antinociception alone but significantly delayed morphine tolerance when co-administered chronically at 0.6 mg/kg. CSF glycine levels increased following NFPS treatment. Chronic treatment with either NFPS doses failed to affect the motor function of the animals at the tested time points.
Conclusions: Simultaneous administration of GlyT1 inhibitors with opioid analgesics maintains antinociceptive effect of opioids. The observed effect could be related to the regulation of glycine at the vicinity of spinal iNMDARs, in particular the extrasynaptic GluN2B which is implicated in the mechanism for opioid analgesic tolerance.
Fund: FK_138389