Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice
14 affiliations
- 1Department of Psychological and Brain Sciences, University of Toronto Mississauga, Mississauga, ON, Canada
- 2Department of Psychology, University of Toronto
- 3Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada
- 4Department of Psychology, McGill University, Montreal, QC, Canada
- 5Department of Psychology, McGill University
- 6Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
- 7University of Toronto
- 8Department of Psychology, University of Toronto Mississauga
- 9Department of Cell and Systems Biology, University of Toronto
- 10Department of Psychology, Anesthesia, and Faculty of Dental Medicine, and Alan Edwards Centre for Research on Pain, McGill University
- 11Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada. [email protected]
- 12Department of Psychology, McGill University, Montreal, QC, Canada. [email protected]
- 13Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada. [email protected]
- 14Department of Psychological and Brain Sciences, University of Toronto Mississauga, Mississauga, ON, Canada. [email protected]
Abstract
The nocebo effect, the evil twin 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. Independently, our two laboratories developed unique animal models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by environmental or social cues. We find that both nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This previously unrecognized pathway could represent a promising target for therapeutic interventions in pain-related disorders. One-Sentence Summary Pain expectations, whether environmentally conditioned or socially transmitted, are mediated by a shared neural circuit involving cholecystokinin (CCK) projections from the anterior cingulate cortex (ACC) to the lateral periaqueductal gray (PAG).
Related
- Layer 5 anterior cingulate cortical neurons engage dorsolateral periaqueductal gray excitatory neurons to facilitate the affective component of pain
- Linking anterior cingulate sulcal variability to attention-deficit hyperactivity disorder behavior
- Two-State Effective Connectivity Predicts the effect of Anterior Cingulate Cortex Excitatory / Inhibitory Balance on Posterior Cingulate Cortex
- Anterior cingulate cortex engram drives Post traumatic stress disorder-like memory impairments in a rodent model of traumatic fear
- Anterior cingulate feedback facilitates rapid global context modulation in primary visual cortex
BibTeX
@article{poulson2026cholecystokinin,
title = {{Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice}},
author = {Sandra J. Poulson and Aleksandrina Skvortsova and Fatama Tuz Zahra and Damien C. Boorman and Seyed Asaad Karimi and Lisiê Valéria Paz and Wanning Cui and Antonietta Mandatori and Jacob Burek and Zahra Siddiqi and Maryam I. Fazili and Shivani R Gami and Oakley B. Morgan and Mélanie Di Maria and Anton Dinh and Lianfang Liang and Robert Contofalsky and Jeffrey S. Mogil and Loren J. Martin},
journal = {Nature Communications},
year = {2026},
month = may,
doi = {10.1038/s41467-026-73266-y},
url = {https://doi.org/10.1038/s41467-026-73266-y},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice
AU - Sandra J. Poulson
AU - Aleksandrina Skvortsova
AU - Fatama Tuz Zahra
AU - Damien C. Boorman
AU - Seyed Asaad Karimi
AU - Lisiê Valéria Paz
AU - Wanning Cui
AU - Antonietta Mandatori
AU - Jacob Burek
AU - Zahra Siddiqi
AU - Maryam I. Fazili
AU - Shivani R Gami
AU - Oakley B. Morgan
AU - Mélanie Di Maria
AU - Anton Dinh
AU - Lianfang Liang
AU - Robert Contofalsky
AU - Jeffrey S. Mogil
AU - Loren J. Martin
PY - 2026
DA - 2026/05/20
JO - Nature Communications
DO - 10.1038/s41467-026-73266-y
UR - https://doi.org/10.1038/s41467-026-73266-y
AB - The nocebo effect, the evil twin 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. Independently, our two laboratories developed unique animal models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by environmental or social cues. We find that both nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This previously unrecognized pathway could represent a promising target for therapeutic interventions in pain-related disorders. One-Sentence Summary Pain expectations, whether environmentally conditioned or socially transmitted, are mediated by a shared neural circuit involving cholecystokinin (CCK) projections from the anterior cingulate cortex (ACC) to the lateral periaqueductal gray (PAG).
SN - 2041-1723
ER -