The aim of this study was to investigate role of the N-Methyl-D-Aspartate (NMDA) receptors in the decrease of morphine analgesia in mice after nociceptive sensitization. We used a hot plate test to assess effects of morphine on pain behavior in male NMRI mice. All drugs were administered through an intraperitoneal route. Sensitization schedule composed of 3-days pre-treatment of morphine (20 mg/kg) followed by 5-days washout. The results showed that morphine (5, 7.5, 10 and 15 mg/kg) induced a significant analgesia in normal mice. However, the analgesic effects of morphine significantly decreased at higher dose (15 mg/kg) in sensitized mice. Injections of either a competitive NMDA receptor antagonist, D-AP5 (0, 0.25, 0.5 and 1 mg/kg) or an NMDA receptor channel blocker (30, 60 and 120 mg/kg) alone had no effect on pain behavior. However, injections of D-AP5 (1 mg/kg), along with morphine over 3-days of the sensitization schedule, significantly prevented the decrease in the analgesic effect of the opioid at doses of 7.5 and 10 mg/kg on the hot plate test. Similarly, injections of MgSO4 (120 mg/kg), along with morphine over 3-days of the sensitization schedule, significantly prevented the decrease in analgesic effect of morphine at doses of 10 and 15 mg/kg. It can be concluded that NMDA receptors are influenced by morphine during the sensitization schedule, which in turn may affect morphine analgesia after the schedule. This may further support the potential effectiveness of NMDA blockade during repeated use of morphine for control of chronic pain.
