Medullary Kappa-Opioid Receptor Neurons Inhibit Pain and Itch Through a Descending Circuit

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit pain processing in the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise identities and mechanisms of pain-inhibitory neurons in the RVM have never been identified. We now expose a cellular circuit that inhibits pain and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and pain. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVM KOR neurons inhibit pain and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the PAG that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and pain.