Ligand-specific receptor states: implications for opiate receptor signalling and regulation

Opiate drugs produce their effects by acting upon G protein coupled receptors (GPCRs) and although they are among the most effective analgesics available, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence, respiratory depression, nausea and constipation. As a class, opiates share a common profile of unwanted effects but there are also significant differences in ligand liability for producing these actions. A growing number of studies show that GPCRs may exist in multiple active states that differ in their signalling and regulatory properties and which may distinctively bind different agonists. In this review we summarize evidence supporting the existence of multiple active conformations for MORs and DORs, analyze information favouring the existence of ligand-specific receptor states and assess how ligand-selective efficacy may contribute to the production of longer lasting, better tolerated opiate analgesics.