Cellular and molecular mechanisms of opioid tolerance and dependence

Recent cellular models of opioid tolerance and dependence have incorporated the idea that excitatory amino acid systems may have an important role in these phenomena. Fundytus and Coderre have developed a model that suggests a prominent role for metabotropic glutamate receptors in the initiation and the development of opioid tolerance and dependence. This Commentary briefly reviews Fundytus and Coderre's model of tolerance and dependence, offering comparisons and contrasts with the model of Mao, Price, and Mayer, which suggests a central role for N-methyl-D-aspartate receptors. Strengths and weaknesses of these models are discussed, as well as potential revisions that may lead to a more complete model of these phenomena.