Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists

Alexander Gillis, Arisbel B. Gondin, Andrea Kliewer, many other and Meritxell Canals

Opioids: Efficacy versus bias

Because of its antinociceptive effects, the μ-opioid receptor (MOR) is an important target for pain management, but serious side effects limit the use of drugs that target this GPCR. Because the MOR stimulates intracellular signaling through both G proteins and β-arrestins, G protein–biased agonists have been developed to promote pain relief without causing β-arrestin–associated side effects. Gillis et al. compared the biochemical, signaling, and physiological properties of some G protein–biased MOR agonists with those of unbiased opioids. The observed reductions in side effects could be explained by the low intrinsic efficacy of the biased agonists rather than by their signaling bias per se. These findings suggest possible strategies for developing new MOR agonists that relieve pain with fewer unwanted side effects.