Neural circuit basis of placebo pain relief

Chong Chen, Jesse K. Niehaus, Fatih Dinc, Karen L. Huang, Alexander L. Barnette, Adrien Tassou, S. Andrew Shuster, Lihua Wang, Andrew Lemire, Vilas Menon, Kimberly Ritola, Adam W. Hantman, Hongkui Zeng, Mark J. Schnitzer and Grégory Scherrer ()
Additional contact information
Chong Chen: The University of North Carolina at Chapel Hill
Jesse K. Niehaus: The University of North Carolina at Chapel Hill
Fatih Dinc: Stanford University
Karen L. Huang: The University of North Carolina at Chapel Hill
Alexander L. Barnette: The University of North Carolina at Chapel Hill
Adrien Tassou: The University of North Carolina at Chapel Hill
S. Andrew Shuster: Harvard Medical School
Lihua Wang: Howard Hughes Medical Institute
Andrew Lemire: Howard Hughes Medical Institute
Vilas Menon: Columbia University
Kimberly Ritola: The University of North Carolina at Chapel Hill
Adam W. Hantman: The University of North Carolina at Chapel Hill
Hongkui Zeng: Allen Institute for Brain Science
Mark J. Schnitzer: Stanford University
Grégory Scherrer: The University of North Carolina at Chapel Hill

Nature, 2024, vol. 632, issue 8027, 1092-1100

Abstract: Abstract Placebo effects are notable demonstrations of mind–body interactions1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain—a phenomenon known as placebo analgesia3–6. However, despite the strength of placebo effects and their impact on everyday human experience and the failure of clinical trials for new therapeutics7, the neural circuit basis of placebo effects has remained unclear. Here we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn)—a precerebellar nucleus with no established function in pain. We created a behavioural assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain-relief expectation, providing cellular-level evidence for a role of the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.

Date: 2024
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DOI: 10.1038/s41586-024-07816-z

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