N-METHYL-D-ASPARTATE (NMDA) RECEPTORS, MU-OPIOID AND KAPPA-OPIOID TOLERANCE, AND PERSPECTIVES ON NEW ANALGESIC DRUG DEVELOPMENT

This laboratory perspective reviews the pharmagologic approaches that have been used in preclinical animal models to demonstrate the ability of competitive (LY274614) and noncompetitive (MK801 and dextromethorp han) N-methyl-D-aspartate (NMDA) receptor antagonists to attenuate or reverse the development of morphine tolerance. We provide additional d ata to support previous observations that these NMDA antagonists modul ate morphine (mu) opioid tolerance but do not affect U50488H (kappa(1) ) opioid tolerance. A strategy, which utilizes efficacy as an NMDA rec eptor antagonist and clinical safety, provides the basis for a discuss ion of the clinical potential of dextromethorphan, ketamine, and felba mate as modulators of opioid tolerance in pain patients or opioid addi cts. The potential use of NMDA receptor antagonists and nitric oxide s ynthase (NOS) inhibitors in neuropathic pain is also discussed.