The μ1-opioid receptor binds to morphine molecules. / Juan Gartner, stock.adobe.com
Jena – Genetic changes in opioid receptors in mice can almost completely suppress the development of tolerance to opioids. The effect then continues even with prolonged administration. Now enter Nature Communication Published research shows that the development of opioid tolerance is mediated by opioid receptor phosphorylation and desensitization (2019; doi: 10.1038 / s41467-018-08162-1).
The mechanism for regulating the molecular opioid receptors on nerve cells is far from being understood in detail. "In principle, we distinguish between the two main signaling pathways on opioid receptors: G-protein mediates the effects of painkillers, and binding of phosphate groups and scaffold proteins held to other receptor segments is sensitive," explained Stefan Schulz of University Hospital Jena. This receptor desensitization, a kind of cell protective mechanism against excessive stimulation, has long been the focus of the Schulz research group in their search for mechanisms that weaken the effects of opioids.
Jena scientists can now confirm their assumptions in mouse experiments along with colleagues from Sydney, London and Gainesville in Florida. They change receptors in animals so they no longer have binding sites for phosphate groups. Desensitization is thus no longer possible and receptors are no longer degraded in nerve cells.
Better effects – almost no tolerance
Scientists have now tested the effect of morphine on natural active ingredients and fentanyl synthetic materials which are very effective in genetically modified animals. "Compared with wild type mice, a single dose is much lower to achieve the same level of pain relief, just under 60% for fentanyl, and less than half for morphine. This effect also lasts longer," explained Andrea Kliewer, author of the study first, the result.
Animals with opioid receptors without a phosphorylation site develop almost no habituation to the drug. Andrea Kliewer, Jena University Hospital
To test the effects of habituation, animals were given continuous painkillers for 7 days. After that, 13 times the fentanyl dose is needed to achieve the same analgesic effect in the wild type compared to the first day. In genetically modified mice it is clearly less than twice. Andrea Kliewer: "Animals with opioid receptors without a phosphorylation site develop almost no habituation to the drug. This confirms our assumption that tolerance and desensitization occur through the same molecular mechanism." Modified opioid receptors also provide better pain relief effects.
More than two-thirds of more than 70,000 drug-related deaths in the US in 2017 died from opioid overdoses. The rapid increase in strong analgesic abuse in the past 20 years has even been considered opioid crisis which prompted US President Donald Trump in 2017 to announce a public health emergency. Fatally, victims of opioids almost always become respiratory paralysis.
Side effects remain unchanged, sometimes even worse
The researchers also examined experimental animals for side effects such as respiratory paralysis and constipation and symptoms of dependence and withdrawal. To do so, they noted lung function and levels of impurities, in their behavioral tests they observed animals for signs of addiction and gave their opioid naloxone antagonists to simulate withdrawals.
Surprising results: All undesirable effects still exist, respiratory depression in genetically modified animals is even clearer than in wild type mice. Opioid dose variations in all animals show that the reduction in pain and side effects changes at the same level.
"Our results clearly indicate that the opioid receptor signaling pathway only regulates desensitization and tolerance development, but the side effects and desired dependence and analgesia are mediated through G protein. This is very important for further development of opioid-based analgesics," Schulz stressed. © energy / EB / aerzteblatt.de