Researchers find brain circuit that drives chronic pain and could lead to new treatments

A brain–spinal cord circuit was found to cause chronic pain after injury and could be a target for treatment without affecting normal protective pain, according to a study published April 1 in Nature.

Chronic pain is a major public health issue in the U.S., with an estimated 50 million adults living with it and nearly 19.6 million reporting that it limits their daily lives or work on a regular basis. Research from the National Institutes of Health found that chronic pain develops more often than several other well-known conditions, including diabetes, depression and high blood pressure, and that nearly two out of three people with chronic pain are still dealing with it a year later.

Scientists believe part of the reason pain lingers is that the brain and spinal cord can actually change over time after an injury, becoming more sensitive to signals. This process is known as central sensitization and could help explain why some patients continue to hurt long after their original injury has healed.

Conducted by researchers from Stanford University, the study used genetically engineered mouse models to map how pain signals travel through the brain and spinal cord. The researchers developed new viral tools and modified a type of virus to identify and track specific nerve cells linked to the μ-opioid receptor.

The team combined these tools with fiber photometry to record real-time neural activity and chemogenetic methods to turn neurons on or off. Mice were tested using established pain models, including nerve injury and inflammation, along with behavioral assays such as mechanical sensitivity and cold response tests. By activating or silencing different parts of the circuit, the researchers identified how repeated stimulation drives chronic pain, while acute responses remained mostly unchanged.

Researchers then found a multi-step brain circuit that appears to drive chronic mechanical pain, which could open the door to new treatment options. The circuit runs from the spinal cord up through two regions of the thalamus, into the brain's sensory cortex and back down to the spinal cord through a structure called the lateral superior colliculus.

When scientists blocked any single point along this pathway in mice with nerve or tissue damage, pain hypersensitivity went away completely and normal pain responses came back. The researchers identified about 5,600 spinal-cord-projecting neurons per mouse in the brainstem, and roughly 65% of those carried a mu-opioid receptor. This is the same receptor that morphine targets.

In healthy mice, the circuit had little impact on everyday pain, suggesting it only switches on after an injury occurs. However, when researchers repeatedly triggered the circuit in uninjured mice, lasting pain sensitivity developed. In addition, blocking the circuit reversed pain hypersensitivity even 28 days after nerve injury, a point when morphine typically stops working. Silencing the circuit also reduced the emotional side of pain, including behaviors like excessive paw attention and pain-triggered avoidance.

Researchers noted the circuit is both necessary and sufficient for chronic mechanical pain to develop and persist, making it a promising target for new therapies that could treat chronic pain without interfering with the body's normal pain signals.

Based on methods and the study’s robust results, it was overall strong because of the study’s use of highly precise tools to zero in on a very specific group of brain cells, giving researchers a much clearer view of how chronic pain starts and keeps going than earlier studies could offer. The team also found that blocking this pain circuit did not affect normal pain responses, which is a promising sign that future treatments based on these findings might be able to target chronic pain without causing other problems.

Limitations include the fact that all of the experiments were done in mice. Researchers noted that results from animal studies don’t always carry over to humans. They also pointed out that some parts of the circuit still are not fully understood, and they called for more research to identify the missing pieces, including a group of nerve cells that may act like a "gate" that controls pain signal.