Tolerance to morphine analgesia - Basic issues to consider

There is a growing body of evidence that implicates the role of excitatory amino acids (EEAs), in particular the N-methyl-D-aspartate (NMDA) receptor, in the development of opioid tolerance. In their Focus article, Fundytus and Coderre have proposed a model of opioid tolerance that highlights the importance of metabotropic glutamate receptors (MGluRs) in the contribution of EEAs to opioid tolerance. The authors conclude that drugs that target MGluRs may provide a therapeutic tool for the prevention of tolerance to morphine analgesia in humans. However, although the authors provide clear evidence that MGluRs play a critical role in the development of tolerance to morphine analgesia, we should practice caution in ascribing a single mechanism to a complex phenomenon. The aim of this Commentary is to examine some broader issues that surround tolerance to morphine analgesia to highlight the complexity of the problem.