Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selectiveglutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA

Piotr Popik*, Ewa Kozela, Malgorzata Wróbel, Krystyna M. Wozniak, Barbara S. Slusher

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Inhibition of glutamate carboxypeptidase II (GCP II; NAALADase) produces a variety of effects on glutamatergic neurotransmission. The aim of this study was to investigate effects of GCP II inhibition with the selective inhibitor, 2-PMPA, on: (a) development of tolerance to the antinociceptive effects, (b) withdrawal, and (c) conditioned reward produced by morphine in C57/Blmice. The degree of tolerance was assessed using the tail-flick test before and after 6 days of twice daily (b.i.d.) administration of 2-PMPA and 10 mg/kg of morphine. Opioid withdrawalwas measured 3 days after twice daily morphine (30 or 10 mg/kg) administration, followed by naloxone challenge. Conditioned morphine reward was investigated using conditioned place preference with a single morphine dose (10 mg/kg). High doses of 2-PMPA inhibited the development of morphine tolerance (resembling the effect of 7.5 mg/kg of the NMDA receptor antagonist, memantine) while not affecting the severity of withdrawal. A high dose of 2-PMPA (100 mg/kg) also significantly potentiated morphine withdrawal, but inhibited both acquisition and expression of morphine-induced conditioned place preference. Memantine inhibited the intensity of morphine withdrawalaswellas acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrievalin a simple two-trialtest, nor did it produce withdrawalsymptoms in morphine-dependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

Original languageAmerican English
Pages (from-to)457-467
Number of pages11
JournalNeuropsychopharmacology
Volume28
Issue number3
DOIs
StatePublished - Mar 2003
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by Guilford Pharmaceuticals and by KBN grant 4 P05A 42 17. The authors are grateful to Dr W Danysz, MERZ and Co, Frankfurt/M, Germany for the gift of memantine.

Keywords

  • Antinociception
  • Drug reward
  • Glutamate carboxypeptidase II
  • Memory
  • NMDA receptor antagonist
  • Opioid withdrawaland dependence
  • Tolerance

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