Mice Reveal a Brain Chemical Signal Behind Nocebo Pain

A Nature Communications study in mice traces the nocebo effect, pain made worse by expectation, to a specific chemical messenger moving between two brain regions. The finding, in animals only, names a candidate molecular target rather than a treatment.

Researchers led by Sandra J. Poulson and Loren J. Martin at the University of Toronto Mississauga, working with a McGill University team, reported in Nature Communications on May 20, 2026 that the chemical messenger cholecystokinin (CCK), released from neurons in the anterior cingulate cortex and acting on receptors in the lateral periaqueductal gray, drives nocebo hyperalgesia in mice. The two labs built separate mouse models, one using a learned context cue and one using a social cue from a cagemate, and found both converged on the same circuit and the same chemical.

The nocebo effect describes pain or other symptoms that worsen because a person expects them to, the inverse of the placebo effect. In humans, a 1997 study by Fabrizio Benedetti and colleagues published in the journal Pain had shown that proglumide, a drug that blocks CCK receptors, could abolish nocebo-induced pain increases, but the brain wiring behind that chemistry was not known. The new mouse work fills that gap: blocking CCK receptors, either with systemic proglumide or by injecting it directly into the lateral periaqueductal gray, eliminated the nocebo pain increase in both mouse models without changing the animals' baseline pain sensitivity.

The authors write that this pathway "could represent a promising target for therapeutic interventions in pain-related disorders," language that describes a future possibility for drug development, not a present-day intervention. The study used optogenetic and chemogenetic tools to manipulate the circuit directly in mice, a level of control not available in human brains, and the behavioral measure was mouse pain response to injury, not self-reported human pain.

The researchers say their next step is testing whether the same cingulate-to-midbrain CCK circuit shapes other expectation-driven symptoms beyond pain. For now, the finding stands as a mechanistic account in animals of how a belief about pain becomes a measurable signal in the brain, not as guidance for anyone managing pain in a clinic.