Two distinct neural pathways may make opioids like fentanyl so addictive

A study in mice identified the brain circuits behind reward and withdrawal

A pill bottle with a fentanyl label sits next to several pills and a vial on a table

Fentanyl and other synthetic opioids are highly addictive. Researchers have now identified two neural pathways behind this addiction.

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Fentanyl’s powerful pull comes from both the potent, rapid euphoria people feel while on the drug and the devastating symptoms of withdrawal. Researchers have now zeroed in on brain circuits responsible for these two forces of fentanyl addiction.

The study in mice, reported May 22 in Nature, suggests two distinct brain pathways are in play.

“Addiction is not a simple disorder — it’s very complex and dynamic,” says Mary Kay Lobo, a neuroscientist at the University of Maryland School of Medicine in Baltimore who was not involved with the new research. She appreciates that the study looks not only at reward in the brain, but also at the withdrawal symptoms, which are “this dark side of addiction.”

Fentanyl and other synthetic opioids are highly addictive (SN: 4/28/23). About one of every four fentanyl users becomes addicted. And in 2022 in the United States alone, there were more than 70,000 deaths from synthetic opioid overdoses, primarily fentanyl.

Researchers have known that dopamine-releasing neurons in an area of the midbrain called the ventral tegmental area, or VTA, mediate feelings like euphoria. But the circuits driving withdrawal symptoms were less clear. Such symptoms include nausea, pain, irritability and an inability to feel pleasure.

To find out more, neuroscientist Christian Lüscher of the University of Geneva and colleagues injected mice with fentanyl for three consecutive days then stopped, inducing withdrawal by giving the mice naloxone.

As expected, neurons in the VTA turned on when mice were getting fentanyl. But the team also uncovered some details of how: Fentanyl inhibited neurons that tamp down the activity of the dopamine-releasing neurons in the VTA, effectively allowing the latter to ramp up their production, sending out dopamine en masse and so triggering the drug’s rewarding effects.

After fentanyl and naloxone administration, mice remained still for longer periods and showed jumping behavior typical of withdrawal. Their brains showed increased activity in neurons in the central amygdala, particularly cells that send their connection to areas known to be associated with fear-learning and forming aversive memories.

Looking at these neurons in more detail revealed that they possessed the main receptor known to respond to fentanyl and other opioids. To the team’s surprise, removing this receptor in the VTA of mice eliminated the rewarding effects of the drug but not the withdrawal behaviors. But when the team knocked out the receptor in the central amygdala, the mice jumped less, suggesting this distinct pathway is involved in withdrawal, the team says.

The researchers took the study one step further, genetically engineering mice so that the neurons in the central amygdala could be turned on and off with light. These mice eventually learned to press a lever to get the neurons to turn off, presumably seeking to avoid the associated negative feelings. This further suggests these neurons have a role in the drug’s withdrawal effects.

Understanding these two pathways could lead to the development of better therapies for opioid addiction (SN: 3/31/19). “It’s pie in the sky right now, but there’s always the possibility of using that to develop circuit-specific therapy for people,” says Megan Fox, a neuroscientist at Penn State who was not involved in the work. For example, clinicians seeking to resolve withdrawal symptoms may target the central amygdala specifically.

The next step is to understand how these two circuits interact, and if the same mechanisms are at play in people, Lüscher says. “How are these forces driving someone from a controlled consumption to compulsive consumption?”

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