Peripherally acting NMDA receptor/glycineB site receptor antagonists inhibit morphine tolerance

Wojciech Danysz, Ewa Kozela, Chris G. Parsons, Meik Sladek, Tanja Bauer, Piotr Popik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

The present study focused on the role of peripheral ionotropic N-methyl-d-aspartate (NMDA) receptors in the development of tolerance to morphine-induced antinociception. An initial experiment revealed that NMDA channel blocker memantine, and NMDA receptor/glycineB site antagonist MRZ 2/576 inhibited maximal electroshock-induced convulsions (MES) in female NMR mice with respective potency of 5.93 and 20.8 mg/kg, while other NMDA receptor/glycineB site antagonists MRZ 2/596 and MDL 105,519 were ineffective, supporting lack of CNS activity of the latter two agents. This observation was also supported by blood-brain barrier experiments in vitro. In male Swiss mice, morphine (10 mg/kg) given for 6 days twice a day (b.i.d.) produced tolerance to its antinociceptive effects in the tail-flick test. The NMDA receptor/glycineB site antagonists, MRZ 2/576 at 0.03, 0.1, 0.3 mg/kg and MRZ 2/596 at 0.1, 0.3, 3 and 10 mg/kg attenuated the development of morphine tolerance. Similarly, in male C57/Bl mice, morphine (10 mg/kg) given for 6 days b.i.d. produced tolerance to its antinociceptive effects in the tail-flick test. Like in Swiss mice, in C57/Bl mice morphine tolerance was attenuated by both MRZ 2/576 and MRZ 2/596. Another NMDA receptor/glycine B site receptor antagonist, MDL 105,519 (that very weakly penetrates to the central nervous system) also inhibited morphine tolerance at the dose of 1 but not 0.1 mg/kg. Moreover, both naloxone hydrochloride (5 and 50 mg/kg) and centrally inactive naloxone methiodide (50 mg/kg) inhibited morphine tolerance suggesting the involvement of peripheral opioid receptors in this phenomenon. The present data suggest that blockade of NMDA receptor/glycineB sites in the periphery may attenuate tolerance to the antinociceptive effects of morphine.

Original languageEnglish
Pages (from-to)360-371
Number of pages12
JournalNeuropharmacology
Volume48
Issue number3
DOIs
StatePublished - Mar 2005
Externally publishedYes

Bibliographical note

Funding Information:
The study was supported in part by Institute of Pharmacology Statutory Activity.

Keywords

  • Antinociception
  • Blood-brain barrier
  • Glutamate
  • NMDA receptor/glycine site antagonist
  • Pain
  • Tolerance

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