Modulation of Morphine Analgesia and Tolerance in Rats by NMDA Receptor Antagonists

The efficacy of opioids in chronic pain treatment is limited because of the development of opioid tolerance. We investigated the role of N-methyl-D-aspartate (NMDA) receptor antagonists (NMDAR Ants) in morphine analgesia and tolerance in rats. To induce the morphine tolerance, experimental rats received morphine (50 mg/kg; subcutaneously) once daily for 3 days. After the last dose of morphine was injected on day 4 and morphine tolerance was evaluated, analgesic effects of ketamine, dizocilpine (MK-801, a non-competitive NMDAR Ant), LY235959 (a competitive NMDAR Ant), cis-2,3-piperidinedicarboxylic acid (PDA, an NMDAR agonist), and morphine were estimated with 30-min-long intervals (0, 30, 60, 90, and 120 min) by the tail-flick and hot-plate algesia tests (n = 6 in each studied group). As was found, ketamine, MK-801, and LY235959 significantly attenuated the development of morphine tolerance (P < 0.05). On the other hand, PDA somewhat increased the development of this tolerance, but the difference was not statistically significant (P > 0.05). Our data indicate that NMDAR Ants attenuate the development of morphine tolerance, significantly affecting the effects of morphine analgesia in rats.