The effects of NMDA receptor antagonists on acute mu opioid analgesia in the rat

Mixed research findings have led to a debate regarding the effect ofNMDA receptor antagonists on opiate analgesia. NMDA antagonists have been found to enhance, inhibit or to have no effect on opiate analgesia. Additionally, enhancement has been found in some studies with doses ofNMDA antagonists that produce adverse side effects, while other studies have found enhancement without untoward effects. There is general agreement that NMDA receptor antagonists do not produce analgesic responses by themselves. Most studies exploring this issue have utilized morphine and the potent and selective non-competitive NMDA antagonist MK-801, which has been found to produce PCP-like side effects. This research had 3 goals: 1) to determine if morphine analgesia could be enhanced with NMDA receptor antagonists, including MK-801 and others; 2) to see if this potentiation occurs with a mu opioid agonist besides morphine (fentanyl); and 3) to determine if the effect occurs at doses of the antagonists that don't produce unwanted side effects. The present research used a single protocol to explore the effects of 6 NMDA receptor antagonists that act at various sites on the NMDA receptor complex (MK-801 (0.1 & 0.3 mg/kg i.p.), (+)-HA-966 (10.0 & 30.0 mg/kg i.p.), LY235959 (1.0 & 3.0 mg/kg i.p.), dextromethorphan (10.0 & 30.0 mg/kg i.p.), ifenprodil (1.0 & 3.0 mg/kg i.p.), and memantine (3.0 & 10.0 mg/kg i.p.)) on acute mu opioid (morphine (3.0 mg/kg s.c.) and fentanyl (0.05 mg/kg s.c.)) analgesia in adult male Sprague-Dawley rats using the tail flick test. A single dose of each opiate was used. The low doses of the antagonists, which are known to produce significant neural and behavioral actions at NMDA receptors, had no effect on morphine or fentanyl analgesia. At the higher doses, morphine analgesia was significantly enhanced by LY235959 (3.0 mg/kg), and fentanyl analgesia was significantly enhanced by LY235959 (3.0 mg/kg), dextromethorphan (30.0 mg/kg), and (+)-HA-966 (30.0 mg/kg). Enhancement of analgesia occurred without any apparent adverse side effects. None of the NMDA antagonists affected tail-flick responses on their own, except the higher dose ofLY235959 (3.0 mg/kg), which produced a mild analgesic effect. Since no consistent effects were observed, the data suggest that NMDA receptors are not involved in acute mu opioid analgesia. The mechanisms underlying the enhancement of opiate analgesia by selected NMDA antagonists, such as LY235959, dextromethorphan, and HA-966 remain to be determined.ion.