Descending inhibitory rostral ventromedial medulla neurons cause widespread antinociception and contribute to the pain-inhibits-pain phenomenon

Acute painful stimuli applied to one body site reduce pain at other sites. The circuit basis of this "pain-inhibits-pain" phenomenon, also known as diffuse noxious inhibitory control (DNIC) in animals or conditioned pain modulation (CPM) in humans, is largely unknown. Using anatomical and optogenetic circuit tracing, we identified a population of descending inhibitory neurons of the rostral ventromedial medulla (RVM) that densely and bilaterally innervate the spinal cord along its rostrocaudal axis. Activating these neurons reduced heat and cold sensitivity widely in healthy mice and caused similarly wide-spread antihyperalgesia in chronic pain models, while their silencing evoked mechanical allodynia and spontaneous pain-like behaviors. Noxious stimuli activated subsets of these neurons in the lateral paragigantocellularis nucleus (LPGi), which inhibited nociception upon chemogenetic reactivation. Spinally projecting inhibitory RVM neurons are hence ideally positioned to function as circuit elements of DNIC and CPM, while their dysfunction may contribute to wide-spread chronic pain syndromes.