It's not just in your head: UTM research deepens understanding of 'nocebo' effect

If you’re worried a needle at a doctor’s office is really going to hurt, there’s a good chance it will. 

That’s the nocebo effect, where negative expectations amplify painful sensations – essentially the opposite of the placebo effect, where positive expectations can help relieve pain. 

Just how the nocebo effect works, and what can be done to deal with it, has long been something of a mystery but new research from the University of Toronto Mississauga, in collaboration with colleagues at McGill University, is providing fresh understanding of the phenomenon. 

The researchers have identified a brain pathway through which the neurochemical linked to the nocebo effect travels to increase pain. 

The findings provide the first evidence that a specific brain circuit is a key driver of nocebo-associated pain responses. 

It’s a discovery that could potentially help those who are affected by pain - including those undergoing medical procedures and who live with chronic pain.

“I know a number of people who have gone to the doctors, and if there’s no structural or tissue damage, they are told the pain is imaginary or it’s in their head,” says senior author Loren Martin, a professor in UTM’s department of psychological and brain sciences.

“(This research) is actually tying it to very discrete biology that’s now showing it’s not imagined.”

In their paper published in Nature Communications, the researchers detail findings from experiments conducted independently in UTM and McGill labs.

Working with mice, they uncovered a brain pathway involving the neurochemical cholecystokinin (CCK), which has long been linked to the nocebo effect. However, where CCK acts in the brain and the neural circuits through which it influences nocebo-associated pain have remained largely unknown. 

Researchers found that the neurochemical travels from an area of the brain involved in the emotional aspects of pain to a brain region that helps control how pain signals are processed. 

By blocking CCK signalling within this pathway, the researchers prevented nocebo-associated increases in pain sensitivity. When they activated the signalling within the pathway, it enhanced pain sensitivity. 

The researchers also found that certain cues – like being in an environment where pain was previously experienced – created negative expectations and triggered increased pain sensitivity.

Sandra Poulson, a former U of T psychology graduate student who worked in Martin’s lab and co-authored the research paper, said these cues play a role in the nocebo effect. 

For example, if someone sees another person experience pain from a needle, that individual’s pain is heightened when they get vaccinated.

“It really gives credence to the fact that we pick up subtle little hints in our environment,” she said. “(Those) can really impact how our brain functions, and our sensory system, and make us perceive different things in a different way.”  

Poulson and Martin said they hoped the findings will spark renewed interest in targeting CCK signalling as a treatment strategy. 

Martin said there are two subtypes of CCK receptors, one found predominantly in the brain, and another found throughout the gastrointestinal system. Although drugs that block CCK receptors were investigated decades ago, they never advanced into widely used treatments for pain. 

Identifying the specific brain circuit through which CCK promotes nocebo-associated pain may help guide the development of more targeted therapies for pain, Martin said. 

He added that anxiety might also be “baked into” the brain pathway they discovered and a next step in their research could be to study whether anxiety-like processes engage the same brain pathway that triggers nocebo-associated pain responses. 

“We need to try to disentangle some of those things," he said. "For me, that becomes a really interesting avenue for exploration."