Top-down control of the descending pain modulatory system drives multimodal placebo analgesia.

Placebo analgesia, in which expectation and prior experience suppress pain in response to an inert treatment, is a powerful clinical phenomenon whose causal neural basis remains unclear. By reverse-translating a human placebo paradigm to mice, we identify neural circuits linking the cortex to the brainstem that causally mediate placebo pain relief. Placebo conditioning suppresses both nociceptive and affective-motivational pain behaviors and generalizes to unconditioned forms of pain. Descending neurons in the ventrolateral periaqueductal gray (vlPAG) are indispensable for both morphine and placebo analgesia, but the placebo effect additionally requires medial prefrontal and anterior cingulate cortical inputs to the vlPAG. Conditioning potentiates noxious stimulus-evoked endogenous opioid release in the vlPAG, which causally gates descending pain modulation. Remarkably, conditioning in pain-naive animals produces lasting placebo analgesia after injury. These findings identify a central circuit mechanism of placebo analgesia and suggest a translational strategy in which preventive placebo conditioning can build resilience to pain.