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S C HW E R P U N K T 30 Opiates such as morphine and synthetic opioids remain the most important painkillers in the treatment of pain, for example, after surgery or when having cancer. However, their use is severely restricted by a reduced respiration and represents a huge potential for addicti- on, too. The risk of these side effects is increased by a habituation effect. De- veloping tolerance means that the dose may need to be increased ten times to achieve the desired level of pain relief. These are key factors in deaths caused by overdose of opioids. The number of Why the pain does not subside Effective painkillers are a real blessing for medicine—but they also have a clear down- side. Taken over a certain period of time, they lose their effect and can lead to addiction. A team of scientists from Jena, Sydney, Melbourne, and Marburg has now shed light on molecular details of the development of tolerance to opiates. The results could support the development of synthetic substances with low drug tolerance and reduce addiction potential. BY UTA VON DER GÖNNA those has risen dramatically over the last decade, especially in the United States. Specific docking sites for painkillers on nerve cells For several years, the research group working with Prof. Dr Stefan Schulz at the Jena University Hospital has been researching the molecular mechanis- ms involved in the regulation of opioid receptors—the specific docking sites for these active substances on the surface of nerve cells. »Reducing the sensitivity of receptors in the case of an oversup- ply of neurotransmitters is actually a sensible protection mechanism against long-term stimulation by the cells«, ex- plains the Professor of Pharmacology and Toxicology, the process that increa- singly reduces the effect of painkillers. Once the receptor is stimulated by the active substance, enzymes ensure that phosphate groups are bound to areas of the receptor molecule lying within the cell interior. The scaffold protein arres- tin is then bound to the receptor, which will eventually be incorporated in the cell. »In previous studies, we were able to show that this process is more noticeable in the case of synthetically manufactured highly effective opioids than with the drug morphine, the latter occurring naturally«, explains Stefan Schulz. »The signaling pathways for drug tolerance differ for these groups of active substances.« Drug tolerance mechanisms explained using bio-optical methods Together with the colleagues from Sydney, Melbourne, and Marburg, the Jena-based researchers have now been able to provide further details about the mechanisms involved in the de- velopment of tolerance. They focused their research on the precise spatial and temporal sequences of the binding pro- cesses. »We discovered phosphorylati- on patterns which are highly specific for the different active substances and Dr Elke Miess is lead author of the international study on the desensitization of opioid receptors. Together with her colleagues, she has been able to show that morphine and synthetic opioids have a different habituation effect due to varying mechanisms. F E AT U R E