How opioids get into our cells
Unlike natural opioids, drugs such as morphine or fentanyl penetrate our cells. This could explain their effectiveness, but also their high addictive potential.
The human body naturally produces opioid-like substances such as endorphins, which have a pain-relieving effect. In pain therapy, however, opioid-containing drugs such as morphine or fentanyl are used. Their major disadvantage is that they make you dizzy, can dangerously slow down your breathing and harbour a high risk of addiction. Their excessive abuse causes hundreds of thousands of deaths worldwide every year, in the USA there has been talk of an opioid crisis for years
Researchers at the University of Geneva (UNIGE) have investigated how natural and therapeutically used opioids work at the cellular level. In general, the substances bind to opioid receptors that mediate a variety of physiological functions. Opioids activate these receptors and thereby trigger a series of biochemical reactions that can reduce the sensation of pain and trigger euphoria. In their study published in "Science Advances" that therapeutic opioids penetrate inside the cells and activate opioid receptors there, while natural opioids cannot enter the cells and only activate receptors on the cell surface. The location of the activated receptors could explain why opioid drugs trigger different physiological responses than natural opioids.
The researchers used new molecular tools to investigate the opioid receptors with unprecedented spatial resolution. "Instead of observing changes in cells as a whole, we were able to see in detail what happens at different locations within the cells," explain Arthur Radoux and Lucie Oberhauser, co-authors of the study. "To do this, we developed biosensors with which we were able to detect in living cells whether receptors are activated at certain locations in or on the cells and which ones trigger a reaction." The scientists combined this technique with analyses of gene expression and protein regulation. Depending on where receptors were activated - inside the cell or in the cell membrane - the triggered reaction, i.e. the signals involved in pain relief, changed.
In a second step, the researchers wanted to find out how these different reactions occur. "We focused specifically on membrane lipids, as recent research has shown that they interact with certain signalling molecules and can change the reactions that trigger receptors," says Mira.receptors," says Miriam Stoeber, first author of the study and Assistant Professor at the Department of Cell Physiology and Metabolism at the UNIGE Faculty of Medicine. In fact, the scientists were able to show that lipids surrounding the receptors influence the signalling. This crucial role of lipids could also explain the various effects and side effects of natural substances and those used in therapy. "We now hope to discover whether altered membrane lipids, which occur in metabolic diseases such as diabetes, influence the efficacy and undesirable side effects of opioid-containing drugs," explains Miriam Stoeber. To confirm this hypothesis, they are planning in vivo experiments with the long-term goal of developing therapeutics with better efficacy and fewer side effects.
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Cover image: © Tashatuvango / Getty Images / iStock (detail) Opiates such as morphine are tried and tested painkillers. They contain opium-like active ingredients that occur naturally in the opium poppy.
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