Journal Article

Neural circuit basis of placebo pain relief

Ritola, Kimberly, Chen, Chong, Niehaus, Jesse K., Huang, Karen L., Hantman, Adam W., Schnitzer, Mark J., Scherrer, Grégory, Zeng, Hongkui, Shuster, S. Andrew, Lemire, Andrew, Barnette, Alexander L., Dinc, Fatih, Tassou, Adrien, Wang, Lihua, Menon, Vilas

2024

Overview

Placebo effects are notable demonstrations of mind–body interactions 1 , 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 analgesia 3 – 6 . However, despite the strength of placebo effects and their impact on everyday human experience and the failure of clinical trials for new therapeutics 7 , 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. Analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex neurons that project to the pontine nucleus.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/51 / 14/1 / 14/19 / 14/32 / 14/35 / 38 / 38/91 / 631/378/3917 / 631/378/3920 / 64/110 / 64/60 / 9/74 / Activity patterns / Analgesia / Analgesics / Animals / Anticipation, Psychological - physiology / Brain / Brain slice preparation / Calcium imaging / Calcium Signaling / Cell activation / Cerebellum / Cerebellum - cytology / Cerebellum - physiology / Clinical trials / Cognition - physiology / Cortex (cingulate) / Drug delivery / Electrophysiology / Female / Flooring / Gene Expression Profiling / Gyrus Cinguli - cytology / Gyrus Cinguli - physiology / Humanities and Social Sciences / In vivo methods and tests / Male / Medical imaging / Mice / Mice, Inbred C57BL / Modulation / multidisciplinary / Narcotics / Neural Pathways / Neurogenesis / Neuroimaging / Neuromodulation / Neurons / Neurons - physiology / Neurotransmission / Nuclei (cytology) / Opioid receptors / Pain / Pain - physiopathology / Pain - prevention & control / Pain - psychology / Pain Management - methods / Pain Management - psychology / Pain Management - trends / Pain perception / Pain Perception - physiology / Pain Threshold - physiology / Pain Threshold - psychology / Placebo Effect / Placebos / Pons - cytology / Pons - physiology / Prefrontal Cortex - cytology / Prefrontal Cortex - physiology / Purkinje cells / Purkinje Cells - physiology / Receptor mechanisms / Receptors, Opioid - metabolism / Science / Science (multidisciplinary) / Synaptic Transmission / Transcriptomics