The classic model of GPCR activation proposed that all agonists induce the same active receptor conformation. However, research over the last decade has shown that GPCRs exist in multiple conformations, and that agonists can stabilize different active states. The distinct receptor conformations induced by ligands result in distinct receptor-effector complexes, which produce varying levels of activation or inhibition of subsequent signalling cascades. This concept, referred to as ligand-directed signalling or biased agonism has important biological and therapeutic implications. Opioid receptors are G(i/o) GPCRs and regulate a number of important physiological functions, including pain, reward, mood, stress, gastrointestinal transport and respiration. A number of in vitro studies have shown biased agonism at the three opioid receptors (µ, δ and κ); however, in vivo consequences of this phenomenon have only recently been demonstrated. For the µ and δ opioid receptors, the majority of reported ligand selective behavioural effects are observed as differential adaptations to repeated drug administration. In terms of the κ opioid receptor, clear links between ligand-selective signalling events and specific in vivo responses have been recently characterized. Drugs for all three receptors are either already used or are being developed for clinical applications. There is clearly a need to better characterize the specific events that occur following agonist stimulation and how these relate to in vivo responses. This understanding could eventually lead to the development of tailor-made pharmacotherapies where advantageous drug effects can be selectively targeted over adverse effects.
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.