ACEA-1328, a NMDA receptor/glycine site antagonist, acutely potentiates antinociception and chronically attenuates tolerance induced by morphine

The effect of ACEA-1328, a competitive and systemically bioavailable NMDA r eceptor/glycine site antagonist, was studied on morphine-induced antinocice ption and tolerance in CD-1 mice using the tail flick test. To study the ef fect of acute administration of ACEA-1328 on morphine-induced antinocicepti on, mice were injected with either ACEA-1328 (1, 5, and 10 mg kg(-1)) or Bi s-Tris (0.2 M) immediately followed by an injection of morphine and tested for antinociception 30 min later. ACEA-1328 significantly increased the ant inociceptive potency of morphine. To study the effect of chronic administra tion of ACEA-1328 on morphine-induced antinociception and tolerance, mice w ere treated, either once per day for 9 days or twice daily for 4 days, with ACEA-1328 or with the vehicle. Mice were then, within 1 min, injected dail y with either morphine or saline. On the day of the test, mice were injecte d with only morphine and tested for antinociception 30 min later. In compar ison to the acute effect of ACEA-1328, chronic treatment with the NMDA rece ptor/glycine site antagonist did not affect the antinociceptive potency of morphine. Chronic treatment with morphine, by both methods, produced a sign ificant degree of tolerance. Concurrent administration of ACEA-1328 with th e opioid analgesic completely blocked morphine tolerance. Our results demon strate that acute, but not chronic, treatment with ACEA-1328 increased the antinociceptive potency of morphine. Furthermore, co-administration of the NMDA receptor antagonist with morphine abolished the development of toleran ce. Overall, the data support a growing body of evidence showing that activ ation of the NMDA receptor plays a functional role in opioid-induced antino ciception and tolerance. (C) 1999 Academic Press.