Fentanyl is a highly potent synthetic opioid that has ceased to be used exclusively for medical purposes and has become a lethal drug that causes three-quarters of overdose deaths in the United States. Despite this, we still do not fully understand how opioids affect the brain, which is why scientists at the University of Geneva (UNIGE) have carried out a study that has revealed that fentanyl produces two different effects through the same cellular receptor in different regions of the brain. One of these effects generates intense euphoria, while the other causes an adverse state during withdrawal.
This discovery could explain why people use opioids not only to feel euphoria, but also to avoid withdrawal, which increases their addictive potential. These findings, published in the journal Nature, question current addiction models and open new possibilities to improve substitution treatments and develop analgesics with fewer side effects.
The effects of fentanyl affect two areas of the brain
When fentanyl is administered intravenously, it acts in less than 10 seconds and is between 20 and 40 times more potent than heroin and 100 times more potent than morphine. In addition, it induces an extremely intense feeling of well-being. However, with repeated use, the absence of the drug manifests itself with very unpleasant withdrawal symptoms.
“We speak of positive reinforcement when the pleasurable sensation leads to continued use of the drug, and of negative reinforcement when consumption is carried out to avoid the painful withdrawal syndrome,” explains Christian Lüscher, professor at the Department of Basic Neurosciences at the Faculty of Medicine of UNIGE and the Synapsy Center for Research in Neuroscience for Mental Health, which led this study. “Withdrawal, which appears a few hours after the last dose, manifests itself physically with tremors, excessive sweating and pain, and psychologically with intense discomfort that does not occur with other drugs.”
The results of the study could explain the high addictive potential of opioids to lead people towards irrational consumption
Fentanyl activates dopaminergic neurons in the mesolimbic system, also known as the reward system, which includes the ventral tegmental area and the nucleus accumbens. These neurons release large amounts of dopamine. Normally, dopaminergic neurons are controlled by inhibitory GABA cells, but opioids block these GABA neurons, which increases the activity of dopaminergic neurons and causes euphoria. The key to understanding this is the “mu” opioid receptor.
“Positive and negative reinforcement mechanisms were believed to occur in the same area of the brain, the mesolimbic system. However, our hypothesis suggests that negative reinforcement originates from cells that express the mu receptor in another part of the brain,” comments Fabrice Chaudun, postdoctoral researcher in Christian Lüscher’s laboratory and first author of this study.
Mimic the neural mechanisms of opioids
To test their hypothesis, the scientists performed several behavioral and neural observation experiments. First, they suppressed the mu receptor in the ventral tegmental area of fentanyl-addicted mice. Although the positive reinforcement disappeared, the abstinence remained. “By replicating the experiment in different neuronal networks, we identified a population of cells that express the mu receptor in the central amygdala, related to fear and anxiety,” says Fabrice Chaudun. “By suppressing the mu receptor in these cells, the withdrawal symptoms disappear, but the positive reinforcement does not.”
Thanks to the collaboration with the teams of Brigitte Kiefer and Emanuel Valjent (Universities of Strasbourg and Montpellier) and the use of mouse lines that allow the mu receptor to be eliminated in selected cells, the scientists were able to mimic the neuronal mechanisms of opioids with precision. without precedents. “This is the complexity of brain research,” summarizes Christian Lüscher. “Pharmacological substances activate numerous networks indiscriminately. To understand the links between a substance, the activation of a neural circuit and behavior, we had to combine different techniques to manipulate neurons and networks.”
To confirm their results, the scientists used optogenetics, a technique that allows them to act on individual cells. By stimulating cells in the central amygdala to mimic fentanyl withdrawal, they caused the same symptoms and behaviors in the mice as real withdrawal. Additionally, a device allowed mice to press a lever to stop neuronal stimulation: mice that had not taken fentanyl did so, while those on the drug did not, confirming that the drug acts on the same networks.
These results radically modify the model of understanding opioid addiction. Given that positive and negative reinforcement are mediated by different networks, this could explain the high addictive potential of these substances: the two mechanisms combine to lead people towards irrational consumption. Furthermore, these discoveries will improve substitution treatments and advance research into analgesics without the risk of addiction.
Source: University of Geneva (UNIGE)
