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Placebo analgesia is associated with activity in a highly interconnected neural network distributed throughout the brain. However, this is based on a large body of functional imaging work that primarily relies on correlative measures of neural activity and neurochemical signaling obtained in human subjects, making it challenging to ascribe causal roles to the underlying neural pathways. To address this gap, we developed a mouse model of placebo analgesia and used chemogenetic loss-of-function manipulations to identify the underlying neural circuits. We specifically addressed the role of the descending pain modulatory system (DPMS) and its upstream cortical circuits. We found that chemogenetic inactivation of a subpopulation of excitatory neurons in the ventrolateral periaqueductal gray (vlPAG) abolishes both morphine analgesia and morphine-conditioned placebo analgesia. Placebo, but not morphine analgesia, depends on vlPAG-projecting neurons in the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), but not the anterior insula (AI). For placebo to occur, mPFC-to-vlPAG neurons must be active during conditioning, consistent with a critical role for activity-dependent plasticity in this pathway. Our findings suggest that the vlPAG implements cognitive pain modulation by integrating top-down commands, at least some of which are conveyed directly from the cortex. Grant support from Rita Allen Foundation (non-profit) NIDA grant (R00 DA 034648) Klingenstein-Simons Foundation (non-profit).
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