An opioid efficacy switch for reversible optical control of analgesia.

The mu-opioid receptor (MOR) is a major target for pain treatment, but its effectiveness is limited by dangerous side effects. However, the systemic administration of opioids makes it difficult both to decipher their underlying mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse effects. Here, we develop a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" (AM-3) that interconverts from low to high efficacy in response to light to enable optical control of MOR signaling. Structural analysis of the low ("trans") and high ("cis") efficacy states of AM-3 bound to the MOR reveals distinct binding modes, with each state driving unique ligand, receptor, and G protein dynamics. In mice, AM-3 drives reversible and repeatable optical control of antinociception across pain models with a reduced side effect profile owing to its limited brain accumulation and its ability to be locally activated.