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

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

Research output: Contribution to journalArticle

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/Bl mice. 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 withdrawal was 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 withdrawal as well as acquisition and expression of morphine-induced conditioned place preference. In addition, 2-PMPA did not affect learning or memory retrieval in a simple two-trial test, nor did it produce withdrawal symptoms in morphine-dependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

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

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Glutamate Carboxypeptidase II
Morphine Dependence
Reward
Morphine
Memantine
Opioid Analgesics
Substance Withdrawal Syndrome
Naloxone
N-Methyl-D-Aspartate Receptors
Synaptic Transmission

ASJC Scopus subject areas

  • Pharmacology

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Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA. / Popik, Piotr; Kozela, Ewa; Wróbel, Malgorzata; Wozniak, Krystyna M.; Slusher, Barbara.

In: Neuropsychopharmacology, Vol. 28, No. 3, 03.2003, p. 457-467.

Research output: Contribution to journalArticle

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