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 morphinedependent, placebo-challenged mice. Results suggest involvement of GCP II (NAALADase) in phenomena related to opioid addiction.

Glutamate Mechanisms Underlying Opiate Memories

“…NMDA-R antagonists block both the acquisition and expression of morphine CPP (Tzschentke and Schmidt 1995;Tzschentke and Schmidt 1997;Popik et al 1998Popik et al , 2003aSuzuki et al 2000;Papp et al 2002;Ribeiro Do Couto et al 2004;Yonghui et al 2006;Rezayof et al 2007;Zarrindast et al 2007;Heinmiller et al 2009;Kao et al 2011;Ma et al 2011b). These effects are at least partly mediated by NR2B-containing NMDA-Rs, as NR2B-selective antagonists, such as ifenprodil, are capable of producing comparable effects (Suzuki et al 1999;Narita et al 2000;Ma et al 2006Ma et al , 2011b.…”

“…Because NMDA-R and AMPA-R antagonists also block the expression of CPP (Layer et al 1993;Tzschentke and Schmidt 1997;Popik et al 1998;Papp et al 2002;Popik et al 2003a;Harris et al 2004;Yonghui et al 2006), their role clearly extends beyond primary reward. NR2B-containing NMDA-R antagonists are capable of reducing the expression of morphine CPP when they are administered during opiate abstinence (without explicit extinction training) (Ma et al 2011b).…”

Reinstatement of Morphine-Conditioned Reward is Blocked by Memantine

“…The place preference apparatus consisted of three rectangular arms (30 Â 15 Â 20 cm 3 ) spaced at 120 1 from each other, which were all accessible from a triangular (central) platform (Popik et al, 2003). The apparatus was made of plastic and the three arms differed in distinctive visual, tactile, and olfactory cues.…”

“…In opioiddependent individuals, treatment with memantine, an N-methyl-D-aspartate (NMDA) channel blocker (Parsons et al, 1999) attenuated the severity of opioid withdrawal syndrome and drug craving, and it increased the retention in treatment (Bisaga et al, 2001;Krupitsky et al, 2002). In laboratory animals, compounds that inhibit glutamatergic neurotransmission diminish the expression of conditioned place preference induced by morphine and cocaine (Popik and Danysz, 1997;Bisaga and Popik, 2000;Kotlinska and Biala, 2000;Suzuki et al, 2000;Popik et al, 2003). However, these effects are short-lived and their relevance to the study of relapse mechanisms is not clear.…”

Conditioned rewarding effects of morphine and methadone in mice pre-exposed to cocaine

“…The CPP apparatus consisted of 3 rectangular arms (30 × 15 × 20 cm) spaced at 120°from each other, all accessible from a triangular (central) platform [28]. The apparatus was made of opaque plastic material (Metaplex) and the three arms differed in distinctive visual, tactile and olfactory cues.…”