Identifying ligand-specific signalling within biased responses: focus on δ opioid receptor ligands

Opioids activate GPCRs to produce powerful analgesic actions but at the same time induce side effects and generate tolerance, which restrict their clinical use. Reducing this undesired response profile has remained a major goal of opioid research and the notion of biased agonism' is raising increasing interest as a means of separating therapeutic responses from unwanted side effects. However, to fully exploit this opportunity, it is necessary to confidently identify biased signals and evaluate which type of bias may support analgesia and which may lead to undesired effects. The development of new computational tools has made it possible to quantify ligand-dependent signalling and discriminate this component from confounders that may also yield biased responses. Here, we analyse different approaches to identify and quantify ligand-dependent bias and review different types of confounders. Focus is on opioid receptor ligands, which are currently viewed as promising agents for chronic pain management. Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit