Morphine is among the most effective and commonly used analgesics in clinical practice. The main problem with morphine analgesia is a decrease of its effect after repeated administrations. The analgesic effects of morphine are mediated primarily through activation of the mu-opioid receptors; however, alterations in N-methyl-D-aspartate (NMDA) receptor levels have been implicated in the development of morphine tolerance and/or dependence. Therefore, the aim of the present study was to investigate role of the NMDA receptors in the decrease of morphine analgesia after its repeated administrations. We used a hotplate analgesiameter to examine analgesic effect of morphine in male NMRI mice. All drugs were administered through an intraperitoneal route. The results showed that different doses of morphine (5, 7.5, 10, 15 mg/kg) induced a significant analgesia in normal mice. The results also showed that in mice with pretreatment of repeated administrations of morphine (10 mg/kg) for three days followed by five days of no drug treatment, the analgesic effect of morphine was decreased. Injections of a NMDA receptor antagonist, DAP5 (1 mg/kg) along with morphine during 3 days of repeated administrations but not during 5 days of any drug treatment, significantly prevented the decrease in analgesic effect of morphine at doses of 7.5 and 10 mg/kg. Similarly, injections of MgSO4 (120 mg/kg) as a NMDA receptor blocker along with morphine during 3 days of repeated administrations but not during 5 days of any drug treatment significantly prevented the decrease in analgesic effect of morphine at doses of 10 and 15 mg/kg. It can be concluded that during 3 days of repeated administrations, NMDA receptors might be indirectly influenced by morphine that finally result in a decrease in morphine analgesia.
