title: Opioid antinociception, tolerance and dependence: interactions with the N-methyl-D-aspartate system in mice.
abstract: This study explored the involvement of N-methyl-D-aspartate (NMDA) in the effects of μ-opioid agonists. A hot-plate procedure was used to assess antinociception and tolerance in mice in which the NR1 subunit of the NMDA receptor was reduced [knockdown (KD)] to approximately 10%, and in mice treated with the NMDA antagonist, (-)-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959). The μ opioid agonists, morphine, l-methadone and fentanyl, were approximately three-fold less potent in the NR1 KD mice than in wild-type (WT) controls; however, the development of morphine tolerance and dependence did not differ markedly in the NR1 KD and the WT mice. Acute administration of the NMDA antagonist, LY235959, produced dose-dependent, leftward shifts in the morphine dose-effect curve in the WT mice, but not in the NR1 KD mice. Chronic administration of LY235959 during the morphine tolerance regimen did not attenuate the development of tolerance in the NR1 KD or the WT mice. These results indicate that the NR1 subunit of the NMDA receptor does not play a prominent role in μ opioid tolerance.
authors.affiliation: Behavioral Neuroscience Program, Department of Psychology, University of North Carolina, Chapel Hill, North Carolina 27599-3270, USA. ldykstra@unc.edu
authors.forename: Linda A
authors.initials: LA
authors.lastname: Dykstra
authors.forename: Bradford D
authors.initials: BD
authors.lastname: Fischer
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Balter
authors.forename: Fredrick E
authors.initials: FE
authors.lastname: Henry
authors.forename: Karl T
authors.initials: KT
authors.lastname: Schmidt
authors.forename: Laurence L
authors.initials: LL
authors.lastname: Miller
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism; D010146:Pain / Q000188:drug therapy*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists
chemical_list: D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D017450:Receptors, Opioid, mu; D009020:Morphine; C088643:LY 235959