Researchers at Duke University School of Medicine have identified a small group of neurons in the brain that appears to control opioid reward learning without mediating pain relief. The study, published in Nature, used a molecular targeting tool called DART to temporarily block opioid receptors on cholinergic neurons in the nucleus accumbens of mice.
Mice treated with this targeted approach no longer developed a preference for a chamber associated with morphine, a standard measure of reward learning. However, the animals still experienced pain relief from morphine, and dopamine levels in the brain still rose in response to the drug.
The findings challenge earlier research that used genetic techniques to permanently remove opioid receptors from cholinergic neurons at birth. Those studies concluded the neurons were not essential for reward learning, but the Duke team suggests the brain may have compensated for the lifelong genetic change.
Senior author Mike Tadross, M.D., Ph.D., said the results show that dopamine elevation alone is not sufficient for opioid reward learning. A drop in acetylcholine release from this specific neuronal hub also appears to be required.
The nucleus accumbens is an evolutionarily ancient brain region shared by mice and humans, raising the possibility that the same mechanism operates in people. However, the researchers emphasize that more work is needed to determine whether the mechanism can be targeted safely with a medication.
The study was led by postdoctoral associate Aryana Yousefzadeh, Ph.D., and published in Nature in 2026. The DART technology used in the experiments was developed in Tadross's laboratory.
New targeting method separates opioid pain relief from reward learning in mice
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