Congratulations to the authors, especially Giulia Livrizzi, who conducted the vast majority of this work while a PhD student in the lab.

Understanding the neural basis of placebo will help us develop better therapies for pain and depression. Capitalizing on placebo can reduce our reliance on dangerous drugs, whereas reducing placebo in clinical trials will help reveal the true efficacy of emerging therapies. 9/9

Interestingly, conditioning appears to prime this circuit through a poorly understood process involving peptidergic plasticity. 8/9

Our findings suggest that the vlPAG is a central node in a closed, negative feedback loop through which incoming noxious sensory information is shaped by endogenous opioids to match expectations based on prior experience. 7/9

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