Receptor with addictive potential

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A Receptor with addictive potential

Opioids are both, a curse and a blessing. They can relieve people of pain, but they often come with severe side effects – including dependency. A research team led by Martin Lohse has now investigated the signaling pathways that produce both the desired effects and undesired side effects.

Opioids are used to treat pain when other pain medications or therapies have failed or proved inadequate. They can enable those suffering from pain to lead an active life once again. But there is a downside: painkillers often go hand-in-hand with side effects that severely impair quality of life – such as nausea, drowsiness, constipation, dry mouth, itching, increased sweating or reduced sexual pleasure.

For many patients who are prescribed opioids, the pain relief gradually wanes over time, while the side effects remain in full force. There is also considerable risk of addiction, with approximately one to three percent of patients who regularly take opioids developing a dependency.

An exclusive look at the cell surface
A research team led by Martin Lohse has now explored the signaling cascade that triggers the negative side effects of pain medication. “Our research is accompanied by the great hope that, one day, opioids will be developed that eliminate pain without causing unwanted side effects – including addiction,” explains Jan Möller, PhD student and first author of the study, which was recently published in the journal Nature Chemical Biology. For a long time it was considered impossible to separate the desired effects of opioids from their undesired side effects.

Under a TIRF microscope, Möller and his colleagues observed what happens when opioids reach the membrane of nerve cells. TIRF, which stands for “total internal reflection fluorescence,” is a special method of light microscopy that makes it possible to specifically locate individual receptors on the outer cell envelope. This is where G protein-coupled receptors (GPCRs) are located, which are responsible for transmitting signals from the external environment into the cell – for example sensory perceptions. It is a particular type of these receptors, the µ‑opioid receptor, that is the main target of opioids. They bind to these opioid receptors and produce pain relief. Opioid receptors usually function as monomers – single reactive molecules that sit on the cell surface and send their message into the cell’s interior.

Not all opioids are alike
But different opioids trigger different reactions at the opioid receptors. For example, when the opioid peptide DAMGO encounters these receptors, the TIRF microscope shows that two receptor molecules combine with each other, dimerizing the receptors. The receptors then migrate into the cell’s interior, where they are prepared for reactivation. In the process, beta-arrestin is transported from inside the cell to the cell membrane, where it binds to the dimerized receptors. Beta-arrestin is believed to be the protein that causes side effects and makes people dependent. On the other hand, when the opioid morphine activates these receptors, no dimer formation occurs, the receptors do not migrate into the cell’s interior, and thus they do not become reactivated.

“Despite countless attempts, it has not yet been possible to significantly improve upon morphine as a painkiller,” explains Professor Martin Lohse, the leader of the project that was funded by the U.S. National Institutes of Health (NIH). “But given that we can now see individual receptors and observe their behavior, we hope to make progress in the development of new painkillers.”

Text: Jana Ehrhardt-Joswig

Möller J, Isbilir A, Sungkaworn T, Osberg B, Karathanasis C, Sunkara V, Grushevskyi EO, Bock A, Annibale P, Heilemann M, Schütte C, Lohse MJ (2020) Single-molecule analysis reveals agonist-specific dimer formation of µ‑opioid receptors. Nature Chemical Biology 16: 946–954.
doi: 10.1038/s41589-020‑0566‑1.