Regulation of opioid receptor activities

From the demonstration of the existence of multiple opioid receptors and th e isolation of the endogenous opioid peptides in the brain, it is now clear that the activities of these receptors can be regulated at various levels. The distinct brain regional distribution of the receptor suggests a tight transcriptional regulation. Early findings of alterations in receptor bindi ng associated with tolerance to the opioids implies that the receptor life cycle can be influenced by the presence of agonists. Until the recent repor ted cloning of opioid receptors, the detailed studies of the molecular mech anisms involved in their regulation could not be conducted. With the availa bility of the cDNA clones of the mu-, delta- and kappa-opioid receptors, an d the elucidation of their gene structures, it is now possible to investiga te opioid receptor regulation at various levels, and to identify the specif ic receptors involved in the pharmacological actions of the opioids. It is now also possible to define the receptor domains responsible for the opioid ligand selectivities, agonist activation, and agonist-induced inactivation . Summarized in this report are our past efforts in defining the regulation of opioid receptor activities. Studies using heterologous expression techn iques, mutational analysis of receptors to characterize transcriptional ele ments, and the in vivo manipulation of the receptor gene levels have made i t is possible to determine the mechanisms whereby these receptors are regul ated. Our studies have also identified the unique characteristics of opioid receptors as members of the superfamily of G protein-coupled receptors.