title: Inhibition of morphine tolerance by NMDA receptor antagonists in the formalin test.
abstract: 5-Nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328) was characterized in vitro for antagonism of excitatory amino acid receptors, and subsequently tested in vivo and compared with MK-801 for phencyclidine (PCP)-like motor stimulation, antinociception, and effects on morphine tolerance in mice. Assayed on rat cerebral cortical glutamate receptors expressed in Xenopus oocytes ACEA-1328 showed potent (Kb approximately 40 nM) antagonism at NMDA receptor/glycine sites and moderate (Kb approximately 3 microM) antagonism at non-NMDA receptors. In both cases inhibition was predominantly competitive. ACEA-1328 was weak, or inactive, at NMDA receptor glutamate recognition sites, metabotropic receptors and opioid binding sites. In the formalin and rotarod tests ACEA-1328 and MK-801 produced both antinociception and disturbances of motor coordination. MK-801 caused a PCP-like motor stimulatory effect, whereas ACEA-1328 was devoid of such an effect. In tolerance studies, ACEA-1328 and MK-801 each blocked morphine tolerance in the formalin test, the effect of ACEA-1328 was dose-dependent. Our data contribute to a growing body of evidence which suggests that activation of NMDA receptors is critical for the development of opioid tolerance, and that antagonism at NMDA receptor/glycine sites may have potential as a means of diminishing tolerance with no PCP-like motor stimulatory side effects.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine 92717, USA.
authors.forename: K
authors.initials: K
authors.lastname: Lutfy
authors.forename: K Z
authors.initials: KZ
authors.lastname: Shen
authors.forename: R M
authors.initials: RM
authors.lastname: Woodward
authors.forename: E
authors.initials: E
authors.lastname: Weber
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000502:physiology; D001923:Brain Chemistry; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde; D015870:Gene Expression / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D009865:Oocytes / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics; D014982:Xenopus laevis
chemical_list: C093392:ACEA 1328; D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D011810:Quinoxalines; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D016291:Dizocilpine Maleate; D009020:Morphine