A newly mapped neural circuit may explain how the brain sustains chronic pain long after injury. Targeting this pathway could relieve persistent pain while preserving essential acute pain responses. Credit: Stock
Scientists have identified a previously unknown brain circuit that appears to drive chronic pain, separate from the pathways responsible for immediate, protective pain responses.
A newly mapped 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.
Credit: Courtesy Xiaoke Chen/Stanford University
Scientists have long suspected that certain brain regions, including the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM), play a role in regulating pain. While stimulating this PAG-RVM system can reduce pain, a complete circuit responsible for chronic pain had not been identified.
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.”
Further tests showed the opposite effect. Activating the same circuit in healthy mice created lasting pain sensitivity. Repeated stimulation increased this sensitivity for weeks. “Just activating these neurons is enough to induce a chronic pain state,” Chen said.
The findings confirm that this circuit is active only in chronic pain conditions. “This group of cells is not engaged in normal pain, but only in chronic pain that occurs after injury or inflammation,” Chen said.
The discovery does not replace earlier ideas about the PAG-RVM system. Instead, the two networks may work in opposite ways. The newly identified circuit appears to amplify pain, while the PAG-RVM pathway helps suppress it. “We think that reducing pain and promoting pain are driven by two separate circuits,” Chen said.
Scientists have long suspected that certain brain regions, including the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM), play a role in regulating pain. While stimulating this PAG-RVM system can reduce pain, a complete circuit responsible for chronic pain had not been identified.
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.”
Further tests showed the opposite effect. Activating the same circuit in healthy mice created lasting pain sensitivity. Repeated stimulation increased this sensitivity for weeks. “Just activating these neurons is enough to induce a chronic pain state,” Chen said.
The findings confirm that this circuit is active only in chronic pain conditions. “This group of cells is not engaged in normal pain, but only in chronic pain that occurs after injury or inflammation,” Chen said.
The discovery does not replace earlier ideas about the PAG-RVM system. Instead, the two networks may work in opposite ways. The newly identified circuit appears to amplify pain, while the PAG-RVM pathway helps suppress it. “We think that reducing pain and promoting pain are driven by two separate circuits,” Chen said.
Jamming the chronic pain circuit
With the circuit mapped, researchers are now investigating the molecular changes that activate it. This could lead to drugs that block or disrupt the signals traveling through the pathway, potentially relieving chronic pain without affecting normal pain responses.
Chen’s team is also analyzing genetic data from people with chronic pain to see if similar mechanisms are at work in humans. Confirming this could guide the development of more precise therapies.
The findings also raise a deeper question about why such a circuit exists. Chen suggests it may be related to how the brain detects internal damage, especially since the brain itself does not have pain-sensing neurons. For now, “it’s still a mystery,” he said.
With the circuit mapped, researchers are now investigating the molecular changes that activate it. This could lead to drugs that block or disrupt the signals traveling through the pathway, potentially relieving chronic pain without affecting normal pain responses.
Chen’s team is also analyzing genetic data from people with chronic pain to see if similar mechanisms are at work in humans. Confirming this could guide the development of more precise therapies.
The findings also raise a deeper question about why such a circuit exists. Chen suggests it may be related to how the brain detects internal damage, especially since the brain itself does not have pain-sensing neurons. For now, “it’s still a mystery,” he said.
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