Making opoids more effective pain killers

The m-opioid receptor (MOR) is an important target for pain management and can be activated by natural opioids, like morphine, and synthetic opioids, such as oxycodone and fentanyl. However, the use of these drugs is limited not only by their high potential for abuse and physical dependence, but also for the unwanted side effects that they cause, such as constipation and respiratory depression, the latter of which can lead to death.

In Science Translational Medicine researchers headed by Alexander Gillis report that agonist binding to the MOR can stimulate intracellular signaling through G proteins and proteins called ?-arrestins. Some agonists specifically stimulate signaling through either G proteins or ?-arrestins, a phenomenon known as biased signaling. Because many of the undesirable effects of MOR agonists are caused by signaling through ?-arrestins, G protein-biased agonists have been developed to promote pain relief with reduced side effects.

Using both cell-based assays and mice, Gillis et al. compared the biochemical, signaling, and physiological properties of some G protein-biased MOR agonists with those of opioids that do not bias downstream signaling. The observed reductions in side effects could be explained by the low intrinsic efficacy of the biased agonists (how well they stimulated intracellular signaling) rather than by their signaling bias (which intracellular pathway they stimulated). These findings suggest possible strategies for developing new MOR agonists that relieve pain with fewer unwanted side effects.