Summary: Researchers mapped the precise brain pathway that drives the nocebo effect, the biological phenomenon where negative expectations actively amplify physical pain. The research reveals that anticipation, fear, or social observation triggers the release of a neurochemical called cholecystokinin (CCK).
This chemical travels along a newly identified pathway to turn up the brain’s internal volume on pain sensitivity. The findings provide direct, physical proof that nocebo pain is a real biological response rather than an imagined symptom, offering a new framework to counter anxiety-driven pain amplification.
Key Facts
- The Nocebo Shift: In direct opposition to the well-known placebo effect, where positive outlooks trigger genuine physical relief, the nocebo effect occurs when negative expectations, shaped by verbal suggestion, past trauma, or social observation, spike anxiety and worsen physical pain.
- The Uncoordinated Convergence: Working completely independently and without any prior coordination, labs at Toronto Mississauga and McGill achieved identical scientific breakthroughs, both identifying the neurochemical cholecystokinin (CCK) as the primary driver of the nocebo response.
- Mapping the ACC-to-lPAG Pathway: Investigators successfully tracked the exact path CCK takes through the brain. The chemical acts as a bridge traveling from the anterior cingulate cortex (ACC), which processes the emotional dimensions of pain, down to a midbrain hub called the lateral periaqueductal gray (lPAG), where it directly dial up pain sensitivity.
- Inducing Negative Expectation: Researchers triggered nocebo states in mouse models using two distinct behavioral methods: returning them to an environment where they had previously felt pain (even with no new injury present) or allowing them to physically watch another mouse experience pain.
- Optogenetic and Chemical Overrides: Utilizing advanced behavioral, pharmacological, and light-driven optogenetic tools, scientists proved they could control the nocebo effect at will. Artificially activating the ACC-to-lPAG circuit immediately increased pain sensitivity, while blocking the pathway completely prevented the nocebo response from emerging.
- Destigmatizing Chronic Pain: Senior author Dr. Loren Martin emphasizes that the study validates the authentic lived experiences of chronic pain patients. Because the brain actively constructs this amplified discomfort through specific neural circuitry, nocebo pain is proven to be a real biological event rather than something imagined or exaggerated.
Source: University of Toronto
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.”
Key Questions Answered:
A: It is driven by a specific, physical amplification loop in your brain. When you anticipate pain based on fear, anxiety, or past experiences, your brain’s emotional center (the ACC) releases a neurochemical called CCK. This chemical travels straight down to a midbrain structure called the lPAG, which acts like a physical volume knob, dialing up your body’s sensitivity and making the actual sensation feel significantly worse.
A: The University of Toronto Mississauga and McGill University independently discovered the exact same neural path without ever coordinating their research. By using light-activated optogenetic tools on mice that were anxious due to a painful memory or from watching another peer suffer, they showed they could switch the nocebo effect on and off. This proves the pain is generated by a concrete, real biological circuit, not a figment of a patient’s imagination.
A: Clinicians have long observed that fear and anxiety make a patient’s real-world symptoms and treatment outcomes much worse. Now that scientists have isolated the exact CCK chemical pathway responsible for this amplification, researchers can focus on developing targeted therapies to block this specific circuit. This holds the potential to disconnect anxiety from pain, keeping negative thoughts from physically sabotaging a patient’s recovery.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this pain and neurology research news
Author: Julia Le
Source: University of Toronto
Contact: Julia Le – University of Toronto
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice” by Sandra J. Poulson, Aleksandrina Skvortsova, Fatama Tuz Zahra, Damien C. Boorman, Seyed Asaad Karimi, Lisiê V. Paz, Wanning Cui, Antonietta Mandatori, Jacob Burek, Zahra Siddiqi, Maryam I. Fazili, Shivani R. Gami, Oakley B. Morgan, Mélanie Di Maria, Anton Dinh, Lianfang Liang, Robert Contofalsky, Jeffrey S. Mogil & Loren J. Martin. Nature Communications
DOI:10.1038/s41467-026-73266-y
Abstract
Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice
The nocebo effect, opposite of the better-known placebo effect, in which anticipation of harm worsens pain and other symptoms, is increasingly thought to be responsible for poor clinical outcomes.
In humans, nocebo hyperalgesia (i.e., increased pain sensitivity) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet, the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to a lack of appropriate animal models.
Here, we developed distinct mouse models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by contextual or social cues.
We find that these nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This pathway could represent a promising target for therapeutic interventions in pain-related disorders.
