Researchers at Duke University School of Medicine announced on Aug. 7 that they have identified a small group of brain cells that play an important role in opioid reward learning, a process believed to lay the foundation for addiction. The findings, published in Nature, represent a step toward separating opioids' pain-relieving benefits from their addictive potential.
The study focused on how opioids interact with different types of neurons in the brain. Opioids are known to relieve pain by binding to receptors in the spinal cord and peripheral nervous system, but they also affect the brain by altering dopamine and other chemicals involved in how pain is perceived. These effects can lead the brain to associate drug use with desirable outcomes—a process called reward learning—which may contribute to addiction.
In experiments with mice, researcher Dayne Tadross and colleagues found that controlling morphine's effects specifically within neurons that release acetylcholine prevented drug-related associations underlying reward learning. Blocking morphine's action in these neurons did not interfere with its ability to relieve pain or elevate dopamine levels elsewhere 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." He added, "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."
Previous studies had suggested cholinergic neurons were not essential for opioid reward learning because researchers used genetic techniques removing opioid receptors from these cells at birth; over time, compensation may have masked their role. Using a molecular targeting tool developed at Duke called DART, Tadross's team created a version of naloxone acting only on cholinergic neurons within the nucleus accumbens while leaving other opioid signaling intact. Mice treated this way no longer developed preferences for environments associated with morphine but still experienced pain relief.
Tadross said earlier studies likely missed this effect due to compensatory changes over time: "We essentially repeated the same experiment, but with better tools." While these results were observed in mice, researchers note that humans share similar neural structures, and further investigation will be needed before clinical applications can be considered.
