Evidence for opiate-activated NMDA processes masking opiate analgesia in rats

The acute interaction between opioid receptors and N-methyl-D-aspartate (NM DA) receptors on nociception was examined in rats using tail-flick and paw- pressure vocalisation tests. When injected at various times (1 to 6 h) afte r morphine (5 to 20 mg/kg, i.v.) or fentanyl (4 X 40 mu g/kg, i.v.), the op ioid receptor antagonist naloxone (1 mg/kg, s.c.) not only abolished the op iate-induced increase in nociceptive threshold, but also reduced it below t he basal value (hyperalgesia). The noncompetitive NMDA receptor antagonist MK-801 (0.15 or 0.30 mg/kg, s.c.) prevented the naloxone-precipitated hyper algesia and enhanced the antinociceptive effects of morphine (7.5 mg/kg, i. v.) and fentanyl (4 X 40 mu g/kg, i.v.). These results indicate that the an tinociceptive effects of morphine and fentanyl, two opiate analgesics widel y used in humans in the management of pain, are blunted by concomitant NMDA -dependent opposing effects which are only revealed when the predominant an tinociceptive effect is sharply blocked by naloxone. This study provides ne w rationale for beneficial adjunction of NMDA receptor antagonists with opi ates for relieving pain by preventing pain facilitatory processes triggered by opiate treatment per se. (C) 1999 Elsevier Science B.V. All rights rese rved.