Iv. Belozertseva et al., Antinociceptive activity of combination of morphine and NMDA receptor antagonists depends on the inter-injection interval, EUR J PHARM, 396(2-3), 2000, pp. 77-83
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.