Opioid Receptor Signaling and Regulation

Abstract:

Opioid receptors are transmembrane proteins that have been shown to be the targets of alkaloids isolated from the opium poppy, Papaver somniferum. The identification of the opioid receptor by ligand–receptor‐binding assays has led to the discovery of the first class of endogenous drug molecules: enkephalin and endorphins. From the discovery of these endogenous gene products and the varied pharmacological responses, multiple opioid receptors were defined and characterized. Since the identification of the receptor by binding assay, opioid receptor has been considered to belong to the membrane receptor superfamily, the G‐protein‐coupled receptor (GPCR). Until the successful cloning of one of the receptor types, δ‐opioid receptor (DOR), by Evans and Kieffer in 1992 (Evans et al., 1992; Kieffer et al., 1992), the eventual properties of the receptor remained elusive. Since then, much is now known about the receptor structure involved in ligand binding, signaling, and cellular control of the receptor. Several recent reviews have summarized the receptor structures/activities relationship and the ligands’ selectivity studies (Law et al., 1999; Quock et al., 1999; Chaturvedi et al., 2000; Janecka et al., 2004), and others have described in detail the regulation of receptor signaling (Law et al., 2000e; Waldhoer et al., 2004). Thus, in this review, we will first briefly examine the historical perspectives in the evolution of the concepts of multiple opioid receptor types, and follow with a review on the studies of receptor signaling, with an emphasis on how chronic opioid treatment could alter the potency and efficacy of agonists.