Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval

The actual time-course of morphine antinociception is shorter than what wou ld be predicted from its elimination kinetics, suggesting the presence of a n acute tolerance phenomenon. Since antagonists acting at NMDA subtype of g lutamate receptors were repeatedly shown to prolong acute morphine antinoci ception, acute tolerance may be attributed to hyperactivity of NMDA recepto rs. The ability of various site-selective NMDA receptor antagonists to affe ct morphine antinociception (tail-flick test) was assessed in mice 30 and 1 20 min after acute morphine challenge. Competitive NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphonic acid (D-CP-Pene) (SDZ EAA 494; 0.1-1 mg/kg), low-affinity channel blockers 1-amino-3,5-dimethyl a damantane (memantine) (1-10 mg/kg) and 1-amino-1,3,3,5,5-pentamethyl-cycloh exan hydrochloride (MRZ 2/579) (1-10 mg/kg), glycine site antagonists 5-nit ro-6,7-dichloro1,4-dihydro-2,3-quinoxalinedione (ACEA-1021) (5 or 10 mg/kg) and 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaliono(4,5-b)quinoline- 5-oxi de choline salt (MRZ 2/576) (1-10 mg/kg) were administered intraperitoneall y (i.p.) 15 or 30 min prior to the tail-flick test (i.e., interval between injections of morphine and NMDA receptor antagonist was either 0-15 or 90-1 05 min). ACEA-1021, MRZ 2/576 and to the lesser extent, memantine and MRZ 2 /579 enhanced morphine antinociception when tests were conducted 120 but no t 30 min post-morphine. D-CPPene potentiated morphine antinociception irres pective of the interval between morphine administration and the tail-flick test. The results suggest that NMDA receptor antagonists may restore analge sic activity of morphine in acutely tolerant mice. (C) 2000 Elsevier Scienc e B.V. All rights reserved.