THE EFFECTS OF NMDA RECEPTOR ANTAGONISTS AND NITRIC-OXIDE SYNTHASE INHIBITORS ON OPIOID TOLERANCE AND WITHDRAWAL - MEDICATION DEVELOPMENT ISSUES FOR OPIATE ADDICTION

This article is an exploration of the National Institute on Drug Abuse (NIDA) Technical Review on the role of glutamatergic systems in the d evelopment of opiate addiction. The effects of ''glutamate antagonist' ' medications on opioid tolerance and withdrawal are examined. In rode nts, mu opioid tolerance cart 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), glyc ine antagonists (ACEA-1328), and nitric oxide synthase (NOS) inhibitor s [L-NNA, L-NMMA, methylene blue (MB)]. Similarly, some of the symptom s of opioid withdrawal observed in opioid-dependent rodents also can b e inhibited by noncompetitive NMDA receptor antagonists (MK801, DM, ke tamine), competitive NMDA receptor antagonists (LY274614), glycine ant agonists (felbamate), and NOS inhibitors (L-NNA, L-NMMA, L-NAME, L-NIO , 7-NI, MB). There are some serious toxicological effects associated w ith the administration of some of the noncompetitive NMDA receptor ant agonists in rodent but not in squirrel monkey brain, and some medicati ons 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.