How Placebos Trick the Brain Into Reducing Pain

The placebo effect—one of the most well-known neural pain relief phenomena—has remained poorly understood for centuries. In an important development, researchers at the University of North Carolina at Chapel Hill tricked a bunch of mice into expecting some relief when there wasn’t any, and in doing so, they identified a specific brain circuit that appears to play a crucial role in this process.

The effect, in which a patient shows improvement in their condition despite being given a substance with no actual medicinal properties, has been well documented going back to the 18th century. While previous experiments established that activity in certain parts of the brain correlated with the placebo effect, the exact mechanism for how it works remains a bit of a puzzle. Sure, when a patient responds to a placebo intended to relieve their pain, brain imaging shows activity in the anterior cingulate cortex—a region associated with processing pain—but this explanation remains somewhat vague. The UNCCH scientists believe they’ve narrowed down how this all works.

In their study, published this week in the journal Nature, the scientists trained mice by placing them in two connected chambers for a week. For the first few days, the floors of both chambers were pleasantly warm. Then, the floor of one chamber was made painfully hot, but the mice were able to seek shelter from the pain by scampering to the second chamber. Finally, on the last day, the floors of both chambers were made painfully hot. The mice, having been conditioned to expect relief upon reaching the second chamber, experienced some pain relief by virtue of the placebo effect. Upon reaching the second chamber, and despite it being just as hot as the first chamber, the mice displayed fewer behaviors associated with being hurt, such as jumping and paw licking. 

Importantly, the mice had been injected with a modified virus that allowed the researchers to monitor specific neurons in a region of the brain known as the rostral anterior cingulate cortex and its connections to three other areas. One of those areas, the pontine nucleus, is crucial to learning motor skills and hadn’t previously been found to have a role in pain processing. But as the mice ran to chamber two, the neurons connecting these two areas lit up.

When the researchers artificially activated this neural pathway in a new set of mice who were exposed to sensitivity tests, the mice again displayed fewer of the hurt behaviors, suggesting this neural circuit plays a key role in placebo-induced pain relief. 

In the study, the authors acknowledge that pain is a complicated thing and that the placebo effect in humans may be more complicated than what’s found in mice. But they expressed hope that their work could lead to newer drugs and behavioral therapies for pain relief. 

More: Mole-Rats Are Impervious to Many Types of Pain