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.