NIH researchers tested the common wisdom that opioids act only on the same surface receptors as endogenous opioids. They discovered that opioids, such as morphine and oxycodone, bind to receptors inside neurons—which are not the targets of naturally occurring opioids. The difference in the actions could help guide the design of pain relievers that do not produce addiction or other adverse opioid-related effects.
The researchers used a new type of antibody biosensor—a nanobody—that generates a fluorescent signal when certain proteins are activated. The signal allowed researchers to track chemicals as they move through cells and responded to stimuli.
The first discovery was that the opioid receptors were activated not only on the surface, but also in the endosome, where the mu-receptor remained activated over several minutes. The researchers also found that there are large differences across a range of opioid drugs in how strongly they induce receptor activation in the endosome. Yet another discovery was that the opioid drugs uniquely induce rapid nanobody signaling, within tens of seconds, in the Golgi apparatus. Therapeutic opioids also uniquely activated mu-opioid receptors in Golgi outposts, in the long, branched structures of neurons.
Based on those findings, the researchers hypothesize that current medically used opioids distort the normal time and spatial sequence of mu-opioid receptor activating and signaling. That distortion may provide the mechanistic link, they say, that explains the undesired adverse effects of opioid medicines.