People who suffer from severe pain following a stroke, trauma or cancer know that over time the most effective prescription pain relievers lose their potency. UF Scripps neuroscientist Dr. Kirill Martemyanov and his team sought to better understand how this addiction develops, involving the prescription of higher and higher doses.
The study reveals the key role of the PTCHD1 gene, involved in modifying cholesterol content in the cell membrane. In other words, the research raises the possibility that cholesterol in the cell membrane may affect the response to opioids and possibly other drugs as well.
Cholesterol in Cell Membrane May Affect Response to Opioids
Drug receptors: hundreds of receptors act as binding sites for drugs and biological molecules on the cell surface. Thus, like “receivers”, mu opioid receptors specifically capture morphine or related molecules. “On reception”, the cellular systems involved in pain relief, slowing breathing and even regulating digestion are put into action. About one-third of all drugs act on these receptor sites, called GPCRs, to G-protein coupled receptorswhich makes them of great interest to scientists.
There are thus more than 800 receptors of this type, and understanding how these genes intervene in the regulation of cholesterol and how cholesterol can promote tolerance, may allow a breakthrough in the development of a new class of less “addictive” analgesics. .
The study: By working on the worm C. elegans and adding the mammalian mu opioid receptor to the worms’ genome, in order to make the worms sensitive to painkillers, the researchers found that:
- treating worms with mammalian mu opioid receptors with fentanyl and morphine initially paralyzes them;
- this effect decreases with repeated exposure;
- the worms eventually develop a tolerance;
- Using numerous attempts at genetic modification to silence different genes, one gene encoding a membrane protein stands out, implicated in tolerance/dependence, and its closest “mammalian” version is PTCHD1;
- scientific data indicate that in humans, this gene is involved in neuropsychiatric conditions; moreover, PTCHD1 belongs to a family of genes known to be involved in the regulation of cholesterol accumulation in cell membranes;
- mice engineered to lack PTCHD1 develop no tolerance following repeated exposure to opioids, but also develop extremely few withdrawal symptoms upon discontinuation of treatment.
What role does cholesterol play in opioid tolerance/dependence? The researchers show that the overexpression of PTCHD1 significantly reduces the cholesterol content of cell membranes.
So might enriching the cell membrane with cholesterol be a strategy to reduce opioid addiction?
- Mice treated with simvastatin, a commonly prescribed cholesterol-lowering drug that also increases high-density lipoprotein, or HDL, do indeed show a lack of dependence following repeated exposures to opioids.
Taken together, these results therefore suggest that cholesterol affects cellular receptors either by directly binding to them or by indirectly controlling downstream cellular activities, and in doing so affects the process of opioid addiction, but probably others. medications.
