Scientists have identified a previously unknown brain circuit that appears to drive chronic pain, separate from the pathways responsible for immediate, protective pain responses.
Brain circuit tied specifically to chronic pain could open the door to better treatments for the nearly 60 million Americans affected by long-term pain, according to a study published in Nature.
Researchers found that shutting down the cells driving this circuit reduced chronic pain while leaving acute pain intact, meaning the body could still detect immediate danger.
“A surprise to us was that acute pain and chronic pain can be completely separate,” said senior author Xiaoke Chen, a Wu Tsai Neurosciences Institute affiliate and associate professor of biology at Stanford Humanities and Sciences. “There is a dedicated circuit that only activates after injury, which gives us the opportunity to target the chronic pain component but leave protective acute pain intact.”
The work was partly funded by the NeuroChoice Initiative, a Wu Tsai Neuro Big Ideas in Neuroscience project focused on addiction biology, including risks linked to prescription opioid use for chronic pain.
A misinterpretation in the brain
Pain normally serves as a warning system, helping the body avoid harm and recover from injury. Chronic pain, however, continues long after the initial threat has passed. It can arise from injury, inflammation, or other conditions and is often linked to higher risks of mental health issues and opioid misuse.
One key feature is sensitization, where even mild touch can feel painful. “In chronic pain, the brain misinterprets touch to be a painful stimulus,” said Chen.
Mapping a new pain pathway
To uncover this pathway, Chen’s team started with neurons in the RVM known to contribute to pain sensitization. Using genetic labeling techniques, they marked connected neurons with a fluorescent protein, revealing a looping circuit that begins in the spinal cord, passes through the thalamus, cortex, and brainstem, and returns to the spinal cord.
When researchers chemically turned off this circuit, mice that had shown signs of chronic pain stopped overreacting to gentle touch and responded normally to different levels of stimulation. Their chronic pain diminished, but their ability to sense immediate harm remained.
“When silencing this group of cells, the sensitized pain goes away,” said Chen. “Therefore, the activity of these cells is necessary for injury or inflammation-induced pain sensitization.”
