1 - Opioid Receptors: Gene Structure and Function

Summary

Introduction

Opiates, the prototype of which is morphine, are potent analgesic and addictive drugs that act through opioid receptors (Barnard, 1993; Browstein, 1993). The opioid system plays a major role in pain-controlling systems (Dickenson, 1991) and affective behavior, including motivation and reward (Di Chiara and North, 1992; Koob 1992). It also modulates locomotor activity, learning and memory, neuroendocrine physiology, and autonomic and immune functions (Olson et al., 1996). Three classes of opioid receptors, μ, δ, and κ, have been identified by pharmacologic approaches (Goldstein and Naidu, 1989). Their endogenous ligands are the opioid peptides (enkephalins, endorphins, and dynorphins), which share a common N-terminal sequence (NH₂-Tyr-Gly-Gly-Phe-Met/Leu-COOH), and are encoded by three different genes known as preproopiomelanocortin, preproenkephalin, and prodynorphin (Day et al., 1993; Rossier, 1993; Young et al., 1993). A new class of highly μ-selective endogenous peptides has been discovered recently (Zadina et al., 1997). These short tetrapeptides, called endomorphines, are structurally distinct from opioid peptides (NH₂-Tyr-Pro-Trp/Phe-Phe-CONH₂), and their genes still need to be isolated. The understanding of pain control or drug addiction, and the development of novel classes of analgesic compounds, require a detailed knowledge of the molecular properties of opioid receptors. Although opioid binding sites have been extensively characterized in the last two decades on the basis of opioid ligand pharmacology, the molecular characterization of the receptors has been initiated only recently (Evans et al., 1992; Kieffer et al., 1992).