New research from the University of Colorado Boulder points to a little-known brain circuit that may determine whether short-term pain fades away or becomes a long-lasting problem. The findings suggest that this pathway plays a key role in turning temporary pain into chronic pain that can persist for months or even years.
The study, conducted in animals and published in the Journal of Neuroscience, focused on a region called the caudal granular insular cortex (CGIC). Researchers found that shutting down this circuit can both prevent chronic pain from developing and stop it after it has already begun.
“Our paper used a variety of state-of-the art methods to define the specific brain circuit crucial for deciding for pain to become chronic and telling the spinal cord to carry out this instruction,” said senior author Linda Watkins, distinguished professor of behavioral neuroscience in the College of Arts and Sciences. “If this crucial decision maker is silenced, chronic pain does not occur. If it is already ongoing, chronic pain melts away.”
New Tools Driving a “Gold Rush of Neuroscience”
The work comes at a time of rapid progress in brain research. First author Jayson Ball describes the current moment as a “gold rush of neuroscience,” driven by advanced tools that allow scientists to precisely control specific groups of brain cells.
With these techniques, researchers can now pinpoint the exact neural pathways involved in complex conditions like chronic pain. This level of detail could help guide the development of new treatments, including targeted infusions or brain-machine interfaces, which may offer safer alternatives to opioid medications.
“This study adds an important leaf to the tree of knowledge about chronic pain,” said Ball, who earned his doctorate in Watkins’ lab in May and now works for Neuralink, a California-based startup that develops brain-machine interfaces for human health.
When Pain Signals Don’t Shut Off
Chronic pain is a widespread issue. According to the Centers for Disease Control, about one in four adults experience it, and nearly one in 10 say it interferes with their daily lives.
A common feature of nerve-related pain is allodynia, a condition in which even light touch can feel painful.
Short-term and long-term pain behave very differently. Acute pain acts as a warning signal, starting when injured tissue, such as a stubbed toe, sends messages through the spinal cord to the brain. Chronic pain, however, continues even after the injury has healed, creating a kind of false alarm that can last for weeks, months, or years.
“Why, and how, pain fails to resolve, leaving you in chronic pain, is a major question that is still in search of answers,” said Watkins.
Targeting the Brain Pathway That Sustains Pain
Earlier work from Watkins’ lab in 2011 pointed to the CGIC as an important player in pain sensitivity. This small region, about the size of a sugar cube, is located deep within the insula, a part of the brain involved in processing sensations. Studies in people have shown that this area tends to be overactive in those with chronic pain.
Until recently, studying this region in detail was difficult because the only way to affect it was to remove it, which is not a realistic treatment option.
In the new study, the team used fluorescent proteins to track which nerve cells became active after a rat experienced a sciatic nerve injury. They then applied advanced “chemogenetic” methods to turn specific genes on or off within selected neurons.
Their results showed that the CGIC is not very important for handling immediate pain but is essential for keeping pain going over time.
How the Brain Keeps Pain Alive
The researchers found that the CGIC sends signals to the somatosensory cortex, the part of the brain that processes touch and pain. This area then communicates with the spinal cord, effectively instructing it to continue transmitting pain signals.
“We found that activating this pathway excites the part of the spinal cord that relays touch and pain to the brain, causing touch to now be perceived as pain as well,” said Ball.
When the scientists turned off this pathway shortly after injury, the animals experienced only brief pain. In cases where chronic pain had already developed, disabling the circuit caused the pain to stop.
“Our research presents a clear case that specific brain pathways can be directly targeted to modulate sensory pain,” said Ball.
Toward New Treatments for Chronic Pain
Researchers still do not know what triggers the CGIC to begin sending persistent pain signals, and more studies are needed before these findings can be applied to people.
Even so, the work points toward new possibilities for treatment. Ball envisions a future where doctors use targeted injections or infusions to affect specific brain cells without the widespread side effects and risk of addiction associated with opioids. He also suggests that brain-machine interfaces, whether implanted or worn externally, could help manage severe chronic pain.
“Now that we have access to tools that allow you to manipulate the brain, not based just on a general region but on specific sub-populations of cells, the quest for new treatments is moving much faster,” he said.
