Addiction to fentanyl is built on two complementary brain mechanisms: the feeling of pleasure when taking the drug (positive reinforcement) and the withdrawal syndrome when trying to quit it (negative reinforcement). Both processes are led by the same molecule, a neuron receptor called mu opioid, but they take place in different regions of the brain, according to a study in mice published yesterday by the journal Nature.

The research, carried out by Swiss and French scientists, is still preliminary, but the results are promising: by blocking receptors in each brain region, positive and negative reinforcements, i.e. addictive mechanisms, decay. The finding may help develop treatments against addiction to fentanyl, an opioid 50 times more powerful than heroin and the leading cause of more than 100,000 overdose deaths recorded each of the past three years in the United States.

The key fact is that each type of reinforcement follows different neural pathways. Until now it was believed that both the feeling of pleasure and the withdrawal syndrome were related to dopamine, better known as the hormone of happiness. The idea was that using fentanyl triggers the production of this neurotransmitter and that levels drop sharply when it is stopped, causing withdrawal symptoms. A team of researchers led by Christian Lüscher, a neuroscientist expert in addictions at the University of Geneva, has validated the first part of the hypothesis (the release of dopamine as a result of drug use), but proposes a new scenario for the second. “Our findings suggest moving from a model in which negative reinforcement was led by a dopamine-deficient state to a model with a different version of the circuit that originates in the amygdala,” he explains in an email to .

This opens the door to treating the withdrawal syndrome without fueling the pleasure associated with fentanyl use. “It seems possible to develop a replacement medication that mitigates the aversive component without activating the positive reinforcement circuit every time,” describes Lüscher. In his words, the expert draws a hypothetical opiate substitute drug that can attach to the mu receptor and does so only in the neurons of the amygdala.

The researcher from the University of Geneva is, however, careful with the extrapolation and excessive optimism of the findings. “Our study was conducted only in mice and represents primarily a gain in knowledge,” he reasons, “translation [to humans] must begin with functional magnetic resonance imaging in patients suffering from substance use disorder. opiates”.

In the experiment, the scientists measured the brain activity of a group of mice after injecting them with increasing doses of fentanyl over five days. They have seen that the most active region of the brain during administration is the ventral tegmental area (VTA), where dopamine is produced. The drug “wakes up” the neurons responsible for producing it and makes the mice more active.

Instead, by interrupting administration and forcing withdrawal, neural activity shifts to the central amygdala, a region that plays a key role in anxiety disorder. In response, the mice become virtually motionless. They only make small jumps, like spasms, as a result of the lack of the drug in the body.