Using a genetically-encoded opioid sensor developed by @LinTianPhD bit.ly/4i2jHTf, we discovered that the painful test stimulus evokes opioid peptide release in the vlPAG within seconds, but this was only detected after morphine conditioning. 5/9

Using Ca2+ recordings and LOF manipulations, we established an essential role for vlPAG neurons that project to the RVM in both morphine and placebo analgesia. In contrast, we found that cortical input to the vlPAG is only critical for placebo. 4/9

Although we only conditioned the mice to suppress a paw withdrawal (antinociception), the placebo effect extended to unconditioned pain-related behaviors, such as avoidance and escape, indicating that the conditioning protocol produces a general state of analgesia. 3/9

To achieve placebo analgesia in mice, we conditioned them with morphine. This yielded ~50% of the morphine effect on placebo trials! Like most placebo analgesia in humans, the placebo in mice relies on endogenous opioid neuropeptide signaling. 2/9