A new study shows that opioids used to treat pain produce their effects by binding to receptors inside neurons, contrary to conventional wisdom that they act on the same surface receptors as endogenous opioids. This finding could provide insights into how to create pain relievers that do not produce addiction or other adverse effects produced by current medicinal opioids. The study was funded by the National Institute on Drug Abuse (NIDA), part of the NIH, and published in Neuron.
Both naturally occurring opioids and medically used ones bind to the mu-opioid receptors, part of the G protein-coupled receptor (GPCR) family. Leveraging recent advances in understanding the 3D structure of GPCRs, the researchers created an antibody biosensor, called a nanobody, that generates a fluorescent signal when a GPCR is activated, enabling them to track chemicals as they move through cells and respond to stimuli.
Using the nanobody, the researchers observed a naturally occurring opioid binding to and activating the mu-receptor on the neuron surface, with receptor molecules entering the cell inside an endosome. The mu-receptor remains activated over a period of several minutes, itself a new discovery since it was previously believed that the receptor is only activated on the surface of nerve cells.
When the same process was done with opioid medications, the researchers observed a large difference in how strongly different clinically relevant opioid drugs induce receptor activation in endosomes. They also found that opioid drugs induce rapid nanobody signaling, within tens of seconds in the Golgi apparatus in the main neuron body of the neuron. They also found mu-opioid receptors to become activated in response to opioid drugs in the Golgi outposts, long, branched structures of neurons.
The researchers hypothesize that current medically used opioids distort the normal sequence of mu-opioid receptor activation and signaling and may be linked to the undesired side effects of opioid medicine.
Image: Fluorescence micrograph of a neuronal cell body showing the location of opioid receptor activation detected by the new biosensor immediately before (left panel) and 20 seconds after (right panel) application of morphine. Arrow points to the Golgi apparatus, a location within the interior of the cell body at which receptors are activated by morphine (as well as a number of other non-peptide opioid drugs) but not by peptide ligands. Image courtesy of: Courtesy: Drs. Miriam Stoeber and Damien Jullié.