Inhibitory effects of MPEP, an mGluR5 antagonist, and memantine, an N-methyl-D-aspartate receptor antagonist, on morphine antinociceptive tolerance in mice

Ewa Kozela*, Andrzej Pilc, Piotr Popik

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Rationale: 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 rain 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.

Original languageAmerican English
Pages (from-to)245-251
Number of pages7
JournalPsychopharmacology
Volume165
Issue number3
DOIs
StatePublished - Jan 2003
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements Authors want to acknowledge the supply of MPEP from Dr Rainer Kuhn, Pharma Novartis, Basel, Switzerland. This study was supported by KBN grant 4 P05A 025 19 to EK.

Keywords

  • Antinociception
  • Mice
  • Morphine
  • Tail-flick test
  • Tolerance

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