The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction

Neuropsychopharmacology. 1995 Dec;13(4):269-93. doi: 10.1016/0893-133X(95)00140-9.


This article is an exploration of the National Institute on Drug Abuse (NIDA) Technical Review on the role of glutamatergic systems in the development of opiate addiction. The effects of "glutamate antagonist" medications on opioid tolerance and withdrawal are examined. In rodents, mu opioid tolerance can be inhibited by noncompetitive N-methyl D-aspartate (NMDA) receptor antagonists [MK801, dextromethorphan (DM), ketamine, phencyclidine (PCP)], competitive NMDA receptor antagonists (LY274614, NPC17742, LY235959), partial glycine agonists (ACPC), glycine antagonists (ACEA-1328), and nitric oxide synthase (NOS) inhibitors [L-NNA, L-NMMA, methylene blue (MB)]. Similarly, some of the symptoms of opioid withdrawal observed in opioid-dependent rodents also can be inhibited by noncompetitive NMDA receptor antagonists (MK801, DM, ketamine), competitive NMDA receptor antagonists (LY274614), glycine antagonists (felbamate), and NOS inhibitors (L-NNA, L-NMMA, L-NAME, L-NIO, 7-NI, MB). There are some serious toxicological effects associated with the administration of some of the noncompetitive NMDA receptor antagonists in rodent but not in squirrel monkey brain, and some medications induce PCP-like behavioral effects. The medications with the most immediate clinical appeal are those that could be coadministered with methadone to decrease mu opioid tolerance and dependence; they include DM, MB, 7-NI, ACPC, and ACEA-1328.

Publication types

  • Review

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Excitatory Amino Acid Antagonists / adverse effects
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Excitatory Amino Acid Antagonists / toxicity
  • Humans
  • Narcotics / adverse effects*
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Opioid-Related Disorders / drug therapy*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / physiology
  • Receptors, Opioid, delta / drug effects
  • Receptors, Opioid, kappa / drug effects
  • Substance Withdrawal Syndrome / drug therapy*


  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Narcotics
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Nitric Oxide
  • Nitric Oxide Synthase