Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice.
BACKGROUND
Inhibition of N-methyl- D-aspartate (NMDA) receptors by memantine, an NMDA-receptor antagonist, and other antagonists of ionotropic receptors for glutamate inhibit the development of opiate antinociceptive tolerance. The role of metabotropic receptors for glutamate (mGluR) in opiate tolerance is less known.


OBJECTIVE
In the present study, we examined the effect of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), the mGluR type-I (subtype mGluR5) antagonist, as well as the effect of co-administration of low doses of memantine and MPEP on morphine antinociceptive tolerance in mice.


METHODS
Morphine antinociceptive activity was tested twice, before and after chronic morphine administration, in the tail-flick test using a cumulative dose-response protocol. Tolerance was induced by six consecutive days of b.i.d. administration of morphine (10 mg/kg, s.c.). Saline, memantine (7.5 mg/kg and 2.5 mg/kg, s.c.), MPEP (30 mg/kg and 10 mg/kg, i.p.) and the combination of both antagonists at low doses was given 30 min prior to each morphine injection during its chronic administration. A separate experiment assessed the effects of memantine, MPEP and their combination on acute morphine antinociception using a tail-flick test.


RESULTS
MPEP (30 mg/kg but not 10 mg/kg) as well as memantine (7.5 mg/kg but not 2.5 mg/kg) attenuated the development of tolerance to morphine-induced antinociception. When given together, the low doses of MPEP (10 mg/kg) and memantine (2.5 mg/kg) also significantly attenuated opiate tolerance. None of the treatments with glutamate antagonists produced antinociceptive effects or significantly affected morphine-induced antinociception.


CONCLUSIONS
The data suggest that both mGluR5 and NMDA receptors may be involved in the development of morphine antinociceptive tolerance.
Kozela
Ewa
E
Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland. kozela@if-pan.krakow.pl
Pilc
Andrzej
A
Popik
Piotr
P
D000701:Analgesics, Opioid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D010147:Pain Measurement; D011725:Pyridines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013623:Tail; D013997:Time Factors
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D009020:Morphine; C121465:6-methyl-2-(phenylethynyl)pyridine; D008559:Memantine