Brain pathway found for placebo pain relief

A research team led by The University of North Carolina at Chapel Hill has discovered a pain control pathway that is crucial to placebo analgesia — where the expectation of pain relief leads to pain alleviation without therapeutic intervention. Their research, published in Nature, provides a new framework for investigating the brain pathways underlying other mind–body interactions and placebo effects beyond the ones involved in pain.

The placebo effect — feeling an improvement in your health after taking a ‘sham’ treatment — has been documented as a very real phenomenon for decades. This explains why individuals in the control group of clinical trials may feel their symptoms subside; in fact, it’s thought that some individuals in the ‘actual’ treatment group also experience the placebo effect. This is one of the reasons why clinical research of therapeutics is so difficult, and why it’s so important to understand what is happening in the brain of someone experiencing the placebo effect.

UNC’s Associate Professor Greg Scherrer and his team knew the scientific community’s understanding of the biological underpinnings of pain relief through placebo analgesia came from human brain imaging studies that showed activity in certain brain regions, but those studies did not have enough precision to show what was actually happening. So the team designed a set of experiments to learn this in more detail.

First, the researchers created an assay that generates in mice the expectation of pain relief. Then they used a series of experimental methods to study the intricacies of the anterior cingulate cortex (ACC), which had been previously associated with the pain placebo effect. While mice were experiencing the effect, the scientists used genetic tagging of neurons in the ACC, imaging of calcium in neurons of freely behaving mice, single-cell RNA sequencing techniques, electrophysiological recordings and optogenetics. This helped them study the intricate neurobiology of the placebo effect down to the brain circuits, neurons and synapses throughout the brain.

The scientists found that when mice expected pain relief, the rostral anterior cingulate cortex neurons projected their signals to the pontine nucleus, which had no previously established function in pain or pain relief. They also found the expectation of pain relief boosted signals along this pathway.

“There is an extraordinary abundance of opioid receptors here, supporting a role in pain modulation,” Scherrer said. “When we inhibited activity in this pathway, we realised we were disrupting placebo analgesia and decreasing pain thresholds. And then, in the absence of placebo conditioning, when we activated this pathway, we caused pain relief.”

Lastly, the scientists found that Purkinje cells — a distinct class of large branch-like cells of the cerebellum — showed activity patterns similar to those of the ACC neurons during pain relief expectation. Scherrer said this is cellular-level evidence for the cerebellum’s role in cognitive pain modulation.

“That neurons in our cerebral cortex communicate with the pons and cerebellum to adjust pain thresholds based on our expectations is both completely unexpected, given our previous understanding of the pain circuitry, and incredibly exciting,” he said.

“We all know we need better ways to treat chronic pain, particularly treatments without harmful side effects and addictive properties. We think our findings open the door to targeting this novel neural pain pathway to treat people in a different but potentially more effective way.”

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