How neuroscientists are designing a safer opioid

America remains in the grips of an opioid epidemic. Over the past 25 years or so, opioid overdose deaths have been rising steadily, reaching a record 81,806 in 2022, and not budging much since. Drugs like morphine, hydrocodone, and fentanyl are extremely effective at pain management, but they’re also very addictive and, when taken in large doses, deadly.

But what if we could design a drug that has all the pain-dulling benefits of traditional opioids without the dangerous downsides? The findings of a new study published in the journal ACS Central Science suggest researchers are making promising progress.

First, a little lesson in neuroscience: Opioid drugs work by binding to the outside of special receptors located on pain neurons, essentially blocking activity along the brain’s pain circuits. But this turns out to be a rather blunt instrument because those receptors help control other brain functions too, like how we perceive reward. Opioids flood the brain with the feel-good hormone dopamine, “rewarding” the user with euphoria and happiness and leaving them wanting more of that pleasurable sensation.

“We know that when we shut off the checkpoints that control that reward circuit, we start to see reinforcing behavior like addiction,” explains Jay McLaughlin, a professor of pharmacodynamics at the University of Florida and a coauthor on the new study.

These receptors are also located along the circuits that control respiration, and when they’re disrupted the brain stops being able to tell the body when to breathe. “Opioid addicts who are experiencing overdose will report to the emergency room breathing once or twice a minute,” McLaughlin says. This hypoxia—or lack of oxygen—is what kills people.

The team set out to find a drug that would still turn off the pain but leave these other signals alone. They tested 10 compounds and settled on a molecule called RO76 that, when tested in mice, appears to robustly suppress pain just like morphine would, but “doesn’t produce all the other side effects that you would see with a more traditional medication,” McLaughlin says.

In the study, the mice didn’t experience reduced breathing rates, and they showed fewer signs of withdrawal than mice that were given morphine. Withdrawal symptoms can be brutal and keep people in addiction. Reducing such symptoms could be a big step toward breaking the cycle of dependence.

McLaughlin says RO76 works by interacting with a site inside the pain receptors, instead of binding to the outside as other opioids do. This is important, because while the outside of the pain receptor acts as an on-off switch, the site inside acts more like a volume knob, controlling the neuron’s activity with more precision. The theory is that this interaction allows RO76 to self-regulate “in a way that’s much safer,” McLaughlin says.

While RO76 isn’t the first compound shown to behave this way, it’s the first known to also cross the blood-brain barrier, a membrane that separates the brain and the rest of the central nervous system from the bloodstream. This barrier keeps out toxins and pathogens, acting as “evolution’s mechanism for protecting the brain.” But it can also be very effective at preventing some drugs from reaching the brain. RO76 doesn’t seem to be one of them.

The findings need to be validated in additional studies before RO76 could be used in human clinical trials. But if it does prove safe and effective, this novel method of targeting the inside of receptors could have benefits that go well beyond better painkillers, because similar receptors are found throughout the body and are “basically controlling most of our cells,” McLaughlin says. “If we apply this to something outside of the opioid receptors, we may be able to start designing safer medications for everything. We could start to move these strategies into other fields for safer heart medications, safer medications for mental disorders. There are a lot of applications just starting to come out—and that’s really exciting.”