A study published in Nature (DOI: 10.1038/s41586-024-07816-z) reveals the neural circuit basis of placebo pain relief. Researchers identified that the rostral anterior cingulate cortex (rACC) neurons projecting to the pontine nucleus (rACC→Pn) mediate placebo analgesia. Using a mouse model, they demonstrated that expectations of pain relief enhance the activity of these neurons, leading to increased neurotransmission in the pathway. Transcriptomic analysis of Pn neurons showed an abundance of opioid receptors, suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia, while activation elicited analgesia without prior conditioning. Purkinje cells in the cerebellum exhibited activity patterns similar to those of rACC→Pn neurons during pain-relief expectation, indicating the cerebellum's involvement in cognitive pain modulation. These findings suggest that targeting the prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation could be a potential treatment for pain. The study also highlights the role of Oprd1-positive Pn neurons in placebo analgesia and the involvement of the cerebellum in pain-relief expectation. The research provides cellular-level evidence for the cerebellum's contribution to placebo analgesia and suggests that the rACC–ponto–cerebellar pathway is critical for placebo effects. The study bridges the gap between our understanding of the sensory-discriminative and affective-motivational dimensions of pain and the cognitive-evaluative dimension, offering new insights into the neural mechanisms underlying placebo analgesia.A study published in Nature (DOI: 10.1038/s41586-024-07816-z) reveals the neural circuit basis of placebo pain relief. Researchers identified that the rostral anterior cingulate cortex (rACC) neurons projecting to the pontine nucleus (rACC→Pn) mediate placebo analgesia. Using a mouse model, they demonstrated that expectations of pain relief enhance the activity of these neurons, leading to increased neurotransmission in the pathway. Transcriptomic analysis of Pn neurons showed an abundance of opioid receptors, suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia, while activation elicited analgesia without prior conditioning. Purkinje cells in the cerebellum exhibited activity patterns similar to those of rACC→Pn neurons during pain-relief expectation, indicating the cerebellum's involvement in cognitive pain modulation. These findings suggest that targeting the prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation could be a potential treatment for pain. The study also highlights the role of Oprd1-positive Pn neurons in placebo analgesia and the involvement of the cerebellum in pain-relief expectation. The research provides cellular-level evidence for the cerebellum's contribution to placebo analgesia and suggests that the rACC–ponto–cerebellar pathway is critical for placebo effects. The study bridges the gap between our understanding of the sensory-discriminative and affective-motivational dimensions of pain and the cognitive-evaluative dimension, offering new insights into the neural mechanisms underlying placebo analgesia.