UC San Diego

Cognitive pain modulation holds promise as the basis of pain therapies that do not rely on opioid analgesics. In placebo analgesia, prior experience and expectations lead to pain suppression in response to the administration of an inert substance. Placebo analgesia is associated with neural activity and endogenous opioid neuropeptide signaling in cortical and midbrain structures that control pain. Yet, how cortex exerts top-down control over pain modulatory circuits, and whether opioid analgesia relies on the same neural pathways remains unclear. Here we establish a placebo-like analgesia (PLAN) assay in mice that involves expectations about pain and show that both morphine- and placebo antinociception rely on antinociception neurons in the periaqueductal gray (PAG) that projects to the rostroventral medulla (RVM). In contrast, placebo-like antinociception, but not morphine analgesia, involves projections to the PAG from the medial prefrontal (mPFC) and anterior cingulate (ACC) cortices. Using a photoactivatable opioid antagonist to control the timing and location of drug action, we observed placebo analgesia to require endogenous opioid signaling in ACC, mPFC, and PAG. These results indicate that opioid drugs and cortically generated expectations about pain converge on the PAG to produce analgesia. By providing mechanistic explanations for longstanding observations in human subjects, these findings bridge clinical and preclinical studies into placebo analgesia