Increased N-methyl-D-aspartate (NMDA) activity in the mouse spinal cord following morphine does not mediate opioid withdrawal.
N-Methyl-D-aspartate (NMDA) receptors have been proposed to play a role in opioid tolerance and dependence. The present study was designed to determine whether the increased NMDA activity in the spinal cord, unmasked by naloxone in morphine-pretreated mice, reflects activity leading to opioid withdrawal. Behavioral responses to intrathecal injections of NMDA were inhibited by pretreatment (2 h) with morphine (10 mg/kg i.p.), but enhanced following morphine when naloxone was injected together with NMDA. Although injected at doses that inhibited NMDA activity, the excitatory effects of morphine on NMDA-induced behaviors were prevented by dizocilpine (MK-801), a phencyclidine (PCP) ligand, but not by 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1 phosphonic acid (CPP), a competitive NMDA antagonist. MK-801 also inhibited naloxone-induced withdrawal jumping, however, just as CPP failed to affect morphine-induced changes in MMDA-induced behaviors, CPP also failed to inhibit withdrawal jumping. Together these data indicated that withdrawal from acute opioid dependence correlates with, but is not mediated by enhanced NMDA activity.
Department of Veterinary PathoBiology, University of Minnesota, St. Paul.
J S
JS
Kreeger
Yukhananov RYu
A A
AA
Larson
D000704:Analysis of Variance; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D012016:Reference Values; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
D010879:Piperazines; D016194:Receptors, N-Methyl-D-Aspartate; D009270:Naloxone; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D009020:Morphine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid