PhD Scientific Days 2025

Poster Session I. - Q: Neurosciences

On the Role of Pregabalin or Naloxone in Delaying Morphine-Induced Antinociceptive Tolerance and Constipation in Rats

Name of the presenter

Gomaa Nariman

Institute/workplace of the presenter

Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1445 Budapest, Hungary

Authors

Nariman Gomaa¹, Kornél Király¹, Zoltán S Zádori¹, Mahmoud Al-Khrasani¹

1: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, Semmelweis University, Nagyvárad tér 4, H-1445 Budapest, Hungary

Text of the abstract

Abstract:
Introduction: Morphine is a widely used opioid analgesic, but its long-term use is associated with the development of morphine antinociceptive tolerance (MAT) and constipation, which hinder the continuation of treatment with opioid analgesics. These effects arise from various mechanisms related to opioid and non-opioid systems, such as glutamate. N-methyl-D-aspartate (NMDA) receptor antagonists have been approved to delay the development of MAT.
Aims and methods: This study explores the effects of pregabalin and tolperisone on MAT and their mechanisms in male Wistar rats. To assess MAT, the rat tail-flick test was used. Cerebrospinal fluid (CSF) D-serine and glycine levels were assessed by capillary electrophoresis. For morphine-induced constipation (MIC), different doses of naloxone (NX) were combined with morphine to investigate the role of NX in reversing MIC, which was assessed by the charcoal meal test.
Results: Chronic morphine administration (sc., 10 mg/kg, twice daily, for 10 days) caused MAT, as indicated by low tail-flick latency. Oral administration of pregabalin or tolperisone at a dose of 100 mg/kg, twice daily, once combined with morphine, demonstrated that only pregabalin delayed the onset of MAT, which was associated with a decrease in the CSF levels of D-serine but not in glycine levels. Morphine (10 mg/kg) or pregabalin (50 mg/kg) acutely evoked constipation, as indicated by decreased charcoal travel distance. Naloxone (PO., 10 mg/kg) abolished MIC.
Conclusion: Combining pregabalin with morphine delayed the development of MAT by a mechanism involving D-serine, which acts as a co-agonist on the NMDA receptor, thus decreasing the receptor activity. In accordance with the literature, NX can alleviate MIC. Whether NX per se or in combination with pregabalin could delay the development of MAT requires further investigation in future studies.
Funding: The University Research Scholarship Program (EKÖP-24) and SE 250+ Excellence PhD Scholarship.