Cholecystokinin input from the anterior cingulate cortex to the lateral periaqueductal gray mediates nocebo pain behavior in mice

The nocebo effect, opposite of the better-known placebo effect, in which anticipation of harm worsens pain and other symptoms, is increasingly thought to be responsible for poor clinical outcomes. In humans, nocebo hyperalgesia (i.e., increased pain sensitivity) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet, the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to a lack of appropriate animal models. Here, we developed distinct mouse models of CCK-dependent nocebo hyperalgesia in which the expectation of pain was elicited by contextual or social cues. We find that these nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This pathway could represent a promising target for therapeutic interventions in pain-related disorders.