NEWS

• 24 July 2024

How do placebos ease pain? Mouse brain study offers clues

The discovery of a brain circuit involved in the pain-relieving effect of placebos could lead to new treatments.

• By

• Miryam Naddaf

When people take a sugar pill they believe is a painkiller, it can lessen their experience of pain.

Researchers have long known about this phenomenon, called the placebo effect. But the biological mechanisms behind it have remained a mystery. Now, neuroscientists have identified brain circuits in mice that could help to explain how placebos can relieve pain.

Strong placebo response thwarts pain killer trials

In a study published today in Nature1, scientists traced the parts of the brain that were activated in mice conditioned to expect pain relief, mimicking how humans experience the placebo effect when given a pill with no active ingredients. They were surprised to see activity in the cerebellum and brainstem — parts of the brain that are typically associated with movement and coordination, rather than pain perception.

“We had no real insight into how [the placebo effect] was happening and if it was a real phenomenon,” says Clifford Woolf, a neuroscientist at the University of Harvard in Boston, Massachusetts. “I think this has helped us identify, indeed it is a real phenomenon.”

The findings might eventually lead to new ways to treat pain, says study co-author Grégory Scherrer, a neurobiologist at the University of North Carolina at Chapel Hill. “We might have a completely novel type of drug.”

Pain-relief pathway

Imaging studies in people have shown that placebo pain relief is associated with activity in the brainstem and a brain region called the anterior cingulate cortex.

To investigate this further, Scherrer and his team developed an experiment to create a placebo-like expectation of pain relief in mice. Using two chambers, one with a comfortably warm floor and one with a painfully hot floor, they conditioned the animals to expect the pain of stepping on the hot floor to ease when entering the cooler chamber.

Using live imaging tools, the team identified a group of neurons that were active during the placebo experiment. These were located in the Pontine nucleus (Pn), an area in the brainstem that connects the cerebral cortex with the cerebellum, and has not previously been associated with pain.

To further understand the role of these neurons in pain relief, the authors measured the effects of blocking their activity. When their Pn neurons were inhibited, mice moving onto the hot floor were quicker to perform pain-relief behaviours such as licking their paws, rearing and jumping. Mice with activated Pn neurons took longer to lick their paws “because it’s not that painful”, says Scherrer.

Follow-up analysis of 4,932 neuron cells in the Pn revealed that 65% had opioid receptors — the same kind that are activated by powerful painkillers. The neurons with opioid receptors extended to three areas in the cerebellum, which was not previously thought to play a part in the expectation of pain relief. The researchers identified a group of Purkinje cells — the main cells in the cerebellum — that became increasingly active during the placebo experiment.

“There are almost certainly endogenous opioids that are participating in this,” says Woolf.

New targets

The research could open up new avenues for understanding how existing painkillers work and discovering new, more effective ones.

Scientists could explore how to engage the neural circuit in the brainstem and cerebellum without relying on placebo pills. Future studies might find “a way that would make it more reliable [to] activate the body’s own control mechanisms that can suppress the experience of pain”, says Woolf.

Understanding these brain circuits could also shed light on why some pain therapies, such as cognitive behavioural therapies and transcranial magnetic stimulation, actually work.

“The brain is a complicated haystack, and we’re often looking for a needle,” says Tom Wager, a neuroscientist who studies the placebo effect at Dartmouth College in Hanover, New Hampshire. This study “provides a new target that we can look for in human studies”.

Questions remain about what precisely activates the placebo effect in those who experience it. “What we still don’t know is, why does it occur in some individuals and not others, and why it disappears over time,” says Woolf.

doi: https://doi.org/10.1038/d41586-024-02439-w