123 0090-2977/12/4402-0123 © 2012 Springer Science+Business Media, Inc. Neurophysiology, Vol. 44, No. 2, 2012 Modulation of Morphine Analgesia and Tolerance in Rats by NMDA Receptor Antagonists E. Ozdemir, 1 I. Bagcivan, 2 and S. Gursoy 3 Received December 19, 2011. 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. Keywords: analgesia, morphine, NMDA antagonists, ketamine, MK-801. 1 Departments of Physiology, 1 Pharmacology, 2 and Anesthesiology and Reanimation, 3 Cumhuriyet University School of Medicine, Sivas, Turkey. Correspondence should be addressed to E. Ozdemir (e-mail: ercan_ozdemir@hotmail.com). INTRODUCTION The rapid development of tolerance and dependence limits the usefulness of morphine in long-term treatment of painful syndromes. Morphine tolerance is a complex phenomenon, involving the serotonergic and noradrenergic systems [1, 2]. Recently, it was also demonstrated that the nitric oxide–cGMP signal pathway plays a pivotal role in the development of tolerance to the analgesic effect of morphine [3]. Over the past decade, much attention in extensive animal studies has been focused on the potential use of N-methyl-D- aspartate (NMDA) receptor antagonists (NMDAR Ants) as adjuvants to opioids [4, 5]. Combinations of NMDAR Ants and opioid agonists are of clinical interest because NMDA antagonists may potentiate opioid analgesia [6]. As was reported, NMDAR Ants either potentiate [7] or do not affect [8] opioid analgesia in humans. The exact reasons for the discrepancies are not clear, but several factors, namely species, strain, the type of opioid agonist and its dose, the NMDAR Ant and its dose, route of drug administration, type of nociceptive stimulus, and injection-to-test interval, either alone or in combination, might be reasons for the inconsistent findings [9]. It was reported that dizocilpine (MK-801) and dextromethorphan (non- competitive NMDAR Ant) enhanced acute morphine analgesia in male but not in female mice [10, 11]. The lack of enhancement by dextromethorphan in females was estrogen-dependent, as ovariectomized mice showed a male-like enhancement and estrogen replacement reinstated by the female phenotype [9]. In contrast, Nemmani et al. suggested that the competitive NMDA receptor antagonist LY235959 enhanced morphine analgesia equally in both sexes [11]. Antagonists of the glycine site in the NMDA receptor complex also produced no effect [12] or potentiated [13] morphine-induced antinociception in the tail-flick studies. We found only one report describing the effect of pretreatment by a polyamine antagonist (ifenprodil) on morphine antinociception tested in the hot-plate test [14]. Ifenprodil potentiated and prolonged the morphine effects. Ifenprodil antinociception was inhibited by naloxone, suggesting the involvement of opioid receptors and, perhaps, an additive effect with morphine. It is unclear whether the effects of NMDAR Ants on acute morphine analgesia are related to