Neural circuit basis of placebo pain relief

• 成果类型: Article
• 署名作者: Chen, Chong; Niehaus, Jesse K.; Dinc, Fatih; Huang, Karen L.; Barnette, Alexander L.; Tassou, Adrien; Shuster, S. Andrew; Wang, Lihua; Lemire, Andrew; Menon, Vilas; Ritola, Kimberly; Hantman, Adam W.; Zeng, Hongkui; Schnitzer, Mark J.; Scherrer, Gregory
• 署名单位: University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; Stanford University; Stanford University; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Columbia University; Allen Institute for Brain Science; Stanford University; Stanford University; Stanford University; Stanford University; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6823
• DOI: 10.1038/s41586-024-07816-z
• 发表日期: 2024-08-29
• 页码: 1092-+
• 关键词: analgesia; cell; expectations; pathways; calcium; anticipation; mechanisms

摘要

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.