Placebo effects are striking 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 failure of clinical trials for new therapeutics ⁷, the neural circuit basis of placebo effects has remained elusive. 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 pre-cerebellar nucleus with no established function in pain. We created a behavioral 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 of a role for 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.

安慰剂效应是身心相互作用的惊人证明 ^1,2 。在疼痛感知过程中，在没有任何治疗的情况下，对疼痛缓解的预期可以减少疼痛的体验，这种现象称为安慰剂镇痛 ^3–6 。然而，尽管安慰剂效应的强度及其对人类日常经验的影响以及新疗法临床试验的失败 ⁷ ，安慰剂效应的神经回路基础仍然难以捉摸。在这里，我们表明，预期疼痛缓解的镇痛是由投射到桥脑核（rACC→Pn）的头端前扣带皮层（rACC）神经元介导的，桥核核是一个在疼痛中没有确定功能的小脑前核。我们创建了一种行为测定，可以在小鼠身上产生类似安慰剂的预期疼痛缓解效果。神经活动的体内钙成像和脑切片的电生理记录表明，疼痛缓解的预期会增强 rACC→Pn 神经元的活性，并增强该通路中的神经传递。 Pn 神经元的转录组研究揭示了丰富的阿片受体，进一步表明其在疼痛调节中的作用。 rACC→Pn 通路的抑制会破坏安慰剂镇痛并降低疼痛阈值，而激活则在没有安慰剂调节的情况下引起镇痛。最后，浦肯野细胞在疼痛缓解预期期间表现出类似于 rACC→Pn 神经元的活动模式，为小脑在认知疼痛调节中的作用提供了细胞水平的证据。这些发现开启了利用药物或神经刺激靶向前额皮质-桥脑-小脑通路来治疗疼痛的可能性。