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

The nocebo effect, the evil twin of the better-known placebo effect in which anticipation of harm causes that harm, is increasingly thought to be responsible for poor clinical outcomes. In humans, nocebo hyperalgesia (i.e., increased sensitivity to pain) is blocked by proglumide, a cholecystokinin (CCK) receptor antagonist. Yet the neural circuitry underlying nocebo hyperalgesia remains unidentified, largely due to lack of appropriate animal models. Independently, our two laboratories developed unique animal models of CCK-dependent nocebo hyperalgesia in which expectation of pain resulted from environmental or social cues. We find that both nocebo paradigms share a neural circuit involving CCK release from neurons projecting from the anterior cingulate cortex to the lateral periaqueductal gray. This pathway, which had not been previously recognized, could represent a promising target for therapeutic interventions in pain-related disorders.