title: Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance.
abstract: Previously, we have shown that inhibition of the glycine site associated with the N-methyl-D-aspartate (NMDA) receptor is another viable approach to blocking morphine tolerance. In the present study, we sought to investigate the involvement of the NMDA receptor/glycine site in kappa-opioid receptor-mediated antinociception and tolerance in CD-1 mice. In antinociception studies, mice were injected with 5-nitro-6,7-dimethyl-1,4-dihydro-2, 3-quinoxalinedione (ACEA-1328), a systemically bioavailable NMDA receptor/glycine site antagonist, or the vehicle (Bis-Tris, 0.2 M) and then immediately with trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e methanesulfonate (U50,488H), a kappa-opioid receptor agonist. Thirty minutes later, mice were tested for changes in nociceptive responses in the tail flick assay. ACEA-1328, per se, prolonged tail flick latencies with an ED(50) of approximately 50 mg/kg. Concurrent administration of ACEA-1328, at doses that did not produce antinociception, with U50,488H increased the potency of U50,488H in a dose-dependent manner. In tolerance studies, mice were treated, either once a day for 9 days or twice daily for 4 days, with the vehicle or ACEA-1328. Immediately after the initial injection, mice then received an injection of saline or U50,488H. On the test day, mice were injected with U50,488H alone and tested for antinociception 30 min later. Chronic treatment with U50,488H by either method produced tolerance. Unlike the acute effect of the drug, chronic treatment with ACEA-1328 decreased the antinociceptive potency of U50,488H. Taken together, the data suggest that acute and chronic administration of ACEA-1328 differentially affected the antinociceptive effect of U50,488H. Furthermore, the decreased in the potency of U50,488H induced by chronic treatment with ACEA-1328 also confounded the interpretation of the tolerance data.
authors.affiliation: Department of Pharmacology, College of Medicine, University of California, Irvine, CA 92717, USA. klutfy@ucla.edu
authors.forename: K
authors.initials: K
authors.lastname: Lutfy
authors.forename: P
authors.initials: P
authors.lastname: Doan
authors.forename: M
authors.initials: M
authors.lastname: Nguyen
authors.forename: E
authors.initials: E
authors.lastname: Weber
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005998:Glycine / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects*; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D011810:Quinoxalines / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry; D017473:Receptors, Opioid, kappa / Q000819:agonists
chemical_list: C093392:ACEA 1328; D018712:Analgesics, Non-Narcotic; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D005998:Glycine