2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Kozela
Ewa
E
Department of Biochemistry, Laboratory of Behavioral Neuroscience, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland. kozela@rabbit.if-pan.krakow.pl
Wrobel
Malgorzata
M
Kos
Tomasz
T
Wojcikowski
Jacek
J
Daniel
Wladyslawa A
WA
Wozniak
Krystyna M
KM
Slusher
Barbara S
BS
Popik
Piotr
P
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D004361:Drug Tolerance; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy*; D009270:Naloxone / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D014966:Xanthenes / Q000494:pharmacology
C402107:2-(phosphonomethyl)pentanedioic acid; D000596:Amino Acids; D004791:Enzyme Inhibitors; C114624:LY 341495; D009943:Organophosphorus Compounds; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C102718:metabotropic glutamate receptor 3; D009270:Naloxone; D009020:Morphine; D043425:Glutamate Carboxypeptidase II