NEUROBIOLOGICAL MECHANISMS OF OPIOID TOLERANCE AND DEPENDENCE

The multiplicity of opioid receptors (mu, partial derivative, kappa) and the limited knowledge of their coupling mechanisms explain why cellular and biochemical changes underlying opioid tolerance/dependence remain poorly understood. Following chronic exposure to opioids, both down- and up-regulation of opioid receptors can occur, depending on the receptor type and/or the central region examined. As these changes generally appear after the tolerance is installed, they are very likely not responsible for it. Instead, opioid tolerance seems to be associated with some uncoupling (probably functional rather than physical) of the opioid receptors from G proteins normally associated with them, therefore resulting in a loss of the capacity of these proteins to exchange GDP for GTP. However, considerable variations might exist in the mechanisms underlying tolerance from one opioid receptor type to another. With regard to dependence, an increase in adenylate cyclase activity, and therefore of cyclic AMP levels and certain protein kinase activities, have been claimed to be responsible for this phenomenon in some cell types. As highly selective opioid agonists and antagonists are now available, experiments with such compounds are expected to yield more informative data on the consequences of the chronic stimulation of a given receptor type. This should contribute to a better understanding of the biochemical and cellular events really responsible for the development of morphine tolerance and dependence.