title: Morphine tolerance and reward but not expression of morphine dependence are inhibited by the selective glutamate carboxypeptidase II (GCP II, NAALADase) inhibitor, 2-PMPA.
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.
authors.affiliation: Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Kraków, Poland. nfpopik@cyf-kr.edu.pl
authors.forename: Piotr
authors.initials: P
authors.lastname: Popik
authors.forename: Ewa
authors.initials: E
authors.lastname: Kozela
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wróbel
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D043425:Glutamate Carboxypeptidase II; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009021:Morphine Dependence / Q000188:drug therapy / Q000201:enzymology*; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects; D012201:Reward
chemical_list: C402107:2-(phosphonomethyl)pentanedioic acid; D004791:Enzyme Inhibitors; D009943:Organophosphorus Compounds; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II