Abstract

From the demonstration of the existence of multiple opioid receptors and the 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 binding associated with tolerance to the opioids implies that the receptor life cycle can be influenced by the presence of agonists. Until the recent reported cloning of opioid receptors, the detailed studies of the molecular mechanisms involved in their regulation could not be conducted. With the availability of the cDNA clones of the μ-, δ- and κ-opioid receptors, and the elucidation of their gene structures, it is now possible to investigate opioid receptor regulation at various levels, and to identify the specific 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 techniques, mutational analysis of receptors to characterize transcriptional elements, and the in vivo manipulation of the receptor gene levels have made it is possible to determine the mechanisms whereby these receptors are regulated. Our studies have also identified the unique characteristics of opioid receptors as members of the superfamily of G protein-coupled receptors.