An opioid efficacy switch for reversible optical control of peripheral analgesia.

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" ( AM-3 ) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy " trans " and high efficacy " cis " states of AM-3 bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice, AM-3 drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.