Opioids and their complicated receptor complexes

No field more eagerly awaits a molecular clarification for G-protein coupled receptor (GPCR) dimerization than theopioid receptor field. Extensive evidence of pharmacologicaland functional interactions between opioid receptor types hasprimed this field for such a resolution. In retrospect, much ofthe data collected on synergy between different opioid receptortypes may represent the functional correlate for the newlyfound opioid receptor dimerization. While previous reports offunctional synergy have been, for the most part, consistent indemonstrating cross-regulation between two receptor types, the lack of highly receptor-selective ligands allowed skeptics toremain doubtful over the interpretations of these results.Today, two important developments in the opioid receptorfield help reinvigorate the hypothesis of functional, cross-modulating opioid receptor complexes: (1) The existence ofhighly selective ligands which eliminate any possibility ofcross-reactivity between receptor types, and (2) the discoverythat opioid receptors and a number of other GPCRs exist as dimers in biochemical, functional and pharmacological assays.It is with these new tools that we seek to understand themechanisms and implications of dimerization. Initial resultsof these studies have demonstrated that the dimerization ofopioid receptors may help consolidate several pharmacologicalfindings that have remained unanswered. In this review wepresent biochemical, pharmacological and functional evidencefor opioid receptor complexes and add evidence from ourrecent studies on opioid receptor dimerization. We believe athorough understanding of receptor dimerization is crucial inclarifying the mechanism of action of opioids and other drugsand may serve a more practical purpose in aiding thedevelopment of novel therapeutic drugs.