Researchers at Duke University School of Medicine are investigating how to keep opioids' pain-relieving benefits while reducing their addictive potential. In a study published in Nature, they report a step toward that goal.
The team found that a particular small group of brain cells appear to play an important role in opioid reward learning, a process that can lay the foundation for addiction. The study challenges conclusions from earlier studies.
Opioids can relieve pain by binding to receptors in the spinal cord and peripheral nervous system, turning down the volume on pain signals before they reach the brain. But opioids also act in the brain itself, altering the release of dopamine and other chemicals that change how a person interprets pain.
"You may still feel the pain, but you aren't bothered by it," said Mike Tadross, MD, PhD, assistant professor of neurosurgery and senior author of the study. “It’s like if you happen to twist your ankle while running away from a bear; you feel the pain, but you just don't care. That kind of analgesia is unique to opioids.”
But those effects come with risk. The brain can learn to associate the drug with desirable outcomes — a process called reward learning. Those lessons can lead to seeking out the drug, which can contribute to addiction.
In mice, Tadross and colleagues, including postdoctoral associate Aryana Yousefzadeh, PhD, found that controlling morphine’s effects in a group of neurons that release a chemical called acetylcholine prevented the drug-related associations that underlie reward learning. But blocking morphine in these neurons didn’t interfere with its pain-relieving effects or its ability to elevate dopamine in the brain.
"What’s unique about our study is that it shows that dopamine elevation can be separated from learned drug preference," Tadross said. "Dopamine isn’t enough by itself; opioid reward learning also appears to require a drop in acetylcholine, controlled by a small cholinergic hub.”
"That’s really exciting because it suggests that you might retain many of the benefits of opioids — even allowing them to do what opioids are so good at doing: to change how pain is perceived in the brain — while potentially making them less addictive.”
The language of neurotransmitters
Neuroscientists often classify neurons by the neurotransmitters they release. "It's like the language they speak," Tadross said.
Most people are familiar with dopamine, often called the brain's "reward" chemical. Opioids trigger dopamine surges in a brain region called the nucleus accumbens, which plays an important role in motivation, emotion, and learning. Because dopamine rises when opioids are taken, scientists have long viewed it as a major driver of opioid reward learning.
But not all neurons in the nucleus accumbens speak the same chemical “language.” Some communicate using acetylcholine, and for years their role in addiction has been uncertain.
Earlier studies examining these cholinergic neurons suggested they were not essential for opioid reward learning. Researchers reached that conclusion using genetic techniques that permanently removed opioid receptors from the cells at birth, leading many scientists to focus on other parts of the brain.
Tadross suspected the picture might look different if the receptors could be blocked temporarily instead. Using a molecular targeting tool called DART, developed in his lab, the team created a version of the opioid reversal drug naloxone that acted only on cholinergic neurons in the nucleus accumbens while leaving opioid signaling elsewhere intact.
The result? The mice no longer developed a preference for a chamber where they received morphine, a widely used measure of reward learning. But they still got pain relief.
The surprising finding suggests that the opioid-induced drop in acetylcholine release from this small group of neurons may play a critical role in helping the brain form rewarding associations with opioids.
Tadross said those earlier studies likely missed the effect because the brain compensated for the genetic changes over time.
"We essentially repeated the same experiment, but with better tools,” he said.
The nucleus accumbens is an evolutionarily ancient brain region shared by mice and people. Although the study was conducted in mice, that similarity raises the possibility that the same mechanism could influence opioid effects in humans. More research is needed to determine whether it does — and whether the mechanism can be targeted safely with a medication.
Other Duke authors: Haidun Yan, Seung-Hwa Kwak, Yunju Oh, Pyeonghwa Jeong, Vladimir Pogorelov, J. Russell Ravenel, Shaun S.X. Lim, James M. Roach, Brenda C. Shields, Ramona M. Rodriguiz, William C. Wetsel, and Jiyong Hong.
Funding: The National Institutes of Health.