Preclinical Evidence for a Role of Glutamatergic Systems in Opioid Tolerance and Dependence

Opioid tolerance and physical dependence are undesirable consequences of chronic opioid use or misuse. Evidence from rodents, using a variety of modes of drug coadministration, reveals that drugs with glutamatergic antagonist activity at the competitive, noncompetitive, or glycine binding sites of the NMDA receptor complex or inhibitors of certain forms of nitric oxide synthase (NOS) can attenuate the development of morphine tolerance and in some cases reverse established tolerance or dependence. Some of these drugs modulate tolerance and dependence without affecting morphine's analgesic effects, suggesting that they prevent neuronal plasticity associated with adaptive changes mediated by the NMDA/NO cascade. Drugs that have a favorable preclinical safety margin are providing leads for new drugs for clinical evaluation.