The study investigates the neural circuit basis of placebo analgesia, a phenomenon where expectations of pain relief can reduce the experience of pain. The researchers developed a behavioral assay in mice that generates a placebo-like anticipatory pain relief response. They found that this response is mediated by rostral anterior cingulate cortex (rACC) neurons projecting to the pontine nucleus (rACC→Pn), a region with no previously established role in pain. In vivo calcium imaging and electrophysiological recordings showed that expectations of pain relief increase the activity of rACC→Pn neurons and enhance neurotransmission in this pathway. Transcriptomic studies revealed an abundance of opioid receptors in Pn neurons, suggesting their involvement in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, while activation of this pathway elicited analgesia without prior conditioning. Additionally, Purkinje cells in the cerebellum exhibited activity patterns similar to those of rACC→Pn neurons during pain-relief expectation, providing evidence for the cerebellum's role in cognitive pain modulation. These findings suggest that targeting the prefrontal cortico-ponto-cerebellar pathway could be a potential therapeutic approach for pain management.The study investigates the neural circuit basis of placebo analgesia, a phenomenon where expectations of pain relief can reduce the experience of pain. The researchers developed a behavioral assay in mice that generates a placebo-like anticipatory pain relief response. They found that this response is mediated by rostral anterior cingulate cortex (rACC) neurons projecting to the pontine nucleus (rACC→Pn), a region with no previously established role in pain. In vivo calcium imaging and electrophysiological recordings showed that expectations of pain relief increase the activity of rACC→Pn neurons and enhance neurotransmission in this pathway. Transcriptomic studies revealed an abundance of opioid receptors in Pn neurons, suggesting their involvement in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, while activation of this pathway elicited analgesia without prior conditioning. Additionally, Purkinje cells in the cerebellum exhibited activity patterns similar to those of rACC→Pn neurons during pain-relief expectation, providing evidence for the cerebellum's role in cognitive pain modulation. These findings suggest that targeting the prefrontal cortico-ponto-cerebellar pathway could be a potential therapeutic approach for pain management.