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.
New research from the University of Toronto, in collaboration with colleagues at McGill University, is shedding light on how the nocebo effect works - and what might be done to counter it.
The findings, published in Nature Communications , provide the first evidence that a specific brain circuit is a key driver of the nocebo effect, tracing the path of a neurochemical linked to the phenomenon.
It's a discovery that could help those who are affected by pain - including patients undergoing medical procedures and people 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 U of T Mississauga'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."
The neurochemical cholecystokinin (CCK) has long been linked to the nocebo effect, but where it acted in the brain, and through what circuits, had remained largely unknown.
In experiments conducted independently at U of T Mississauga and McGill, researchers mapped how CCK travels from a brain region tied to the emotional experience of pain to another that regulates its signals.
They found that blocking CCK signalling in this pathway prevented a nocebo-related increase in pain sensitivity, while turning it on was enough to ratchet up sensitivity.
The research suggests this pathway can be triggered both by environmental cues, such as being in a place associated with past painful experiences, or social ones, such as seeing someone else's distress.
Sandra Poulson, a co-author of the paper who worked in Martin's lab as a U of T graduate student, said the results show how our brains are highly attuned to signs that pain could be coming.
For example, a vaccination could feel more painful if you've watched the previous patient wince from a needle.
"It really gives credence to the fact that we pick up subtle little hints in our environment," said Poulson, who is currently a postdoctoral fellow at the University of Pennsylvania. "(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 throughout the gastrointestinal system. Drugs blocking CCK receptors were investigated decades ago but never advanced into widely used pain treatments.
Identifying the specific brain circuit behind CCK's role in nocebo-related pain may help guide the development of more targeted therapies, Martin said.
He added that anxiety might also be "baked into" this pathway, and a next step could be to study whether anxiety-like processes engage the same circuit.
"We need to try to disentangle some of those things," he said. "For me, that becomes a really interesting avenue for exploration."
