phenobarbital-sodium and Morphine-Dependence

We have recently reported that conditioned morphine reward and tolerance to its antinociceptive effect, but not expression of morphine dependence, were attenuated by 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a prototypic inhibitor of glutamate carboxipeptidase II (GCP II), which is an enzyme responsible for the supply of glutamate. In the present study, we investigated in more detail the effects of GCP II inhibition on opioid dependence and tolerance to its antinociceptive effect in C57/Bl mice using a novel GCP II inhibitor.. The treatment with 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA; 60 but not 10 or 30 mg/kg) prevented the development of morphine tolerance without affecting acute morphine antinociception. 2-MPPA at 30 and 60 mg/kg did not prevent the development of dependence induced by 10 and 30 mg/kg of morphine. The study on opioid withdrawal syndrome, i.e., expression of opioid dependence, demonstrated that 2-MPPA potentiated jumping behavior and teeth chattering but attenuated chewing and ptosis. None of these opioid withdrawal signs were affected by 2-MPPA in morphine nondependent mice. Pretreatment with the mGluR II antagonist LY341495 (1 mg/kg) reversed the 2-MPPA-induced increase or decrease in opioid withdrawal signs in morphine-dependent mice. 2-MPPA (60 mg/kg) administered for 7 days with morphine did not affect brain concentration of this opiate.. The present findings suggest complex effects of GCP II inhibition on morphine dependence and tolerance and imply a role of mGluR II in the actions of 2-MPPA.

Topics: Amino Acids; Animals; Drug Tolerance; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Male; Mice; Mice, Inbred C57BL; Morphine; Morphine Dependence; Naloxone; Organophosphorus Compounds; Receptors, Metabotropic Glutamate; Xanthenes

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.

Topics: Animals; Carboxypeptidases; Drug Tolerance; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Male; Mice; Mice, Inbred C57BL; Morphine Dependence; Organophosphorus Compounds; Pain Measurement; Reward