Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

Ghasemi, Mehdi; Shafaroodi, Hamed; Nazarbeiki, Saeed; Meskar, Hossein; Ghasemi, Abbas; Bahremand, Arash; Ziai, Pouya; Dehpour, Ahmad Reza

doi:10.1016/j.eplepsyres.2010.06.010

« Previous Next »Epilepsy Research
Volume 91, Issue 1 , Pages 39-48, September 2010

Inhibition of NMDA receptor/NO signaling blocked tolerance to the anticonvulsant effect of morphine on pentylenetetrazole-induced seizures in mice

Mehdi Ghasemi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
- Present address: Institute for Cell Engineering, Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hamed Shafaroodi
- Pharmacology and Toxicology Department, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran
Saeed Nazarbeiki
- School of Medicine, Shahed University of Medical Sciences, Tehran, Iran
Hossein Meskar
- School of Medicine, Shahed University of Medical Sciences, Tehran, Iran
Abbas Ghasemi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
Arash Bahremand
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
Pouya Ziai
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
Ahmad Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
- Corresponding author at: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Poursina Ave., Keshavarz Boulvd., P.O. Box 13145-784, Tehran, Iran. Tel.: +98 21 6611 2802; fax: +98 21 6640 2569.

Received 5 December 2009; received in revised form 31 May 2010; accepted 23 June 2010.

Summary

Although morphine has anticonvulsant effect in several animal models of seizure, its potential clinical application in epilepsy may be hindered by its adverse effects like the phenomenon of opioid tolerance. The present study evaluated the development of tolerance to the anticonvulsant effect of morphine in a model of clonic seizure induced by pentylenetetrazole (PTZ) in male Swiss mice. We also examined whether N-methyl-d-aspartate (NMDA) receptor/nitrergic system blockage was able to prevent the probable tolerance. Our data demonstrated that anticonvulsant effects of a potent dose of morphine (1mg/kg) was abolished in chronic morphine-treated mice (with the same dose of morphine twice daily, 4 days, i.p.). Chronic pretreatment with low and non-effective doses of different NMDA antagonists ifenprodil (0.5mg/kg), MK-801 (0.05mg/kg) and ketamine (0.5mg/kg) as well as the non-selective nitric oxide (NO) synthase inhibitor l-NAME (2mg/kg) inhibited the development of tolerance to the anticonvulsant effect of morphine (1mg/kg). Moreover, a single acute injection of the above mentioned agents at the same doses reversed the expression of tolerance to the anticonvulsant effects of morphine (1mg/kg). These results demonstrate that anticonvulsant effect of morphine can be subject to tolerance after repeated administration. Both development and expression of tolerance are inhibited by NMDA receptor/nitrergic system blockage, suggesting a role for NMDA receptor/NO signaling in the development of tolerance to the anticonvulsant effect of morphine.