Reverse-engineering placebo analgesia.

Placebo analgesia is a widely observed clinical phenomenon. Establishing a robust mouse model of placebo analgesia is needed for careful dissection of the underpinning circuit mechanisms. However, previous studies failed to observe consistent placebo effects in rodent models of chronic pain. We wondered whether strong placebo analgesia can be reverse engineered using general-anesthesia-activated neurons in the central amygdala (CeA) that can potently suppress pain. Indeed, in both acute and chronic pain models, pairing a context with CeA-mediated pain relief produced robust context-dependent analgesia, exceeding that produced by morphine in the same paradigm. CeA neurons receive monosynaptic inputs from temporal lobe areas that could potentially relay contextual cues directly to CeA neurons. However, in vivo imaging showed that CeA neurons were not reactivated in the conditioned context, despite mice displaying a strong analgesic phenotype. This finding suggests that the placebo-context-induced pain relief engages circuits beyond CeA neurons and relies on plasticity in other analgesic and/or nociceptive circuits. Our results show that conditioning with the activation of a central pain-suppressing circuit is sufficient to engineer placebo analgesia and that purposefully linking a context with an active treatment could be a means to harness the power of placebo for pain relief.