Potential Discovery: Understanding How the Placebo Effect Alleviates Pain

A newly identified brain pathway in mice may explain why placebos, or interventions that should have no therapeutic effect, can relieve pain, and the development of drugs that target this pathway could lead to safer alternatives to painkillers such as opioids.

If someone unknowingly takes a sugar pill instead of a painkiller, they still feel better. The placebo effect is a well-known phenomenon in which people's expectations reduce symptoms even in the absence of an effective treatment. “Our brain can solve the pain problem on its own, based on the expectation that a drug or treatment might work,” says Dr. Gregory Scherer At the University of North Carolina at Chapel Hill.

To understand how the brain does this, Scherer and his colleagues recreated the placebo effect in 10 mice using a cage with two chambers: one with a blazingly hot floor and the other with no floor. After three days, the mice learned to associate the second chamber with pain relief.

The researchers then injected molecules into the animals' brains that caused active neurons to light up when viewed under a microscope, and then returned the animals to their cages, but this time they heated both floors.

Although the two chambers were now equally hot, the mice still preferred the second chamber and showed less symptoms of pain, such as licking their paws, while they were there. They also showed more neuronal activity in the cingulate cortex, a brain region involved in processing pain, compared with nine mice that had not been conditioned to associate the second chamber with pain relief.

Further experiments revealed pathways connecting these pain-processing neurons to cells in the pontine nuclei and cerebellum, two brain regions not previously known to play a role in pain relief.

To confirm that this circuit relieved pain, the researchers used a technique called optogenetics, which switches cells on and off with light. This allowed them to activate the newly discovered neural pathway in another group of mice that were placed on a hot floor. On average, these mice took three times longer to lick their paws than mice that didn't have the circuit activated, indicating that they felt less pain.

If this neural pathway explains the placebo effect, “it could open up new strategies for drug development,” he said. Luana Colocca “If we had a drug that could activate the placebo effect, it would be an excellent strategy for pain management,” said University of Maryland researcher David L. Schneider, who was not involved in the study.

“An obvious caveat is that the placebo experience in humans is clearly much more complex. [than in animals]”The pain pathways are very similar to ours,” Scherer said, but because rodents and humans have very similar pain pathways, he believes these findings also apply to humans.