Researchers have a better understanding of the nocebo effect and the neuroscience behind it all. Opposite of the better-known placebo effect, where positive expectations trigger genuine pain relief, the nocebo effect is the experience from negative expectations, created by prior experience, verbal suggestion, or social observation, which can drive anxiety and make pain worse.
A new study published in Nature Communications , by researchers at the University of Toronto Mississauga and McGill University, identified a brain pathway through which negative expectations can amplify pain. The findings, generated independently by the two labs without prior coordination, converged on the neurochemical cholecystokinin (CCK), which has previously been linked to nocebo pain responses in humans.
The researchers identified a specific brain pathway through which CCK acts, travelling from the brain’s anterior cingulate cortex (ACC), a region involved in the emotional dimensions of pain, to a midbrain structure called the lateral periaqueductal gray (lPAG), where it increases pain sensitivity.
Negative expectations were induced either by returning mice to an environment where they had previously experienced pain, even without a new injury, or by allowing them to observe another mouse undergoing pain. Using a combination of behavioural, pharmacological, and optogenetic approaches, the researchers identified and manipulated this pathway directly. Activating the circuit increased pain sensitivity, while blocking it prevented the nocebo effect from emerging.
“Researchers have known for years that CCK is linked to nocebo responses in humans, but our study identifies the specific brain pathway through which this system enhances pain,” said Dr. Loren Martin, professor in the Department of Psychological and Brain Sciences at the University of Toronto Mississauga and one of the study’s senior authors.
The researchers became interested in the nocebo effect because clinicians have long observed that negative expectations, fear, and prior painful experiences can worsen symptoms and treatment outcomes in patients. Although these experiences are important in medicine, the brain processes that cause them to increase pain are still not well understood.
“If we can better understand the circuitry that drives these effects, we may eventually be able to reduce harmful pain amplification in disorders where anxiety, anticipation, and negative expectations worsen symptoms,” Martin said.
The findings may also help reduce stigma surrounding chronic pain and related disorders.
“One important implication of this work is that it helps validate what patients are actually experiencing,” Martin said. “Nocebo-related pain amplification is not simply imagined or exaggerated. The brain is actively generating a real biological pain response through specific neural circuitry.”
Nature Communications
Observational study
Animals
Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice
20-May-2026