General anesthetics activate a potent central pain-suppression circuit in the amygdala

General anesthesia (GA) can produce analgesia (loss of pain) independent of inducing loss of consciousness, but the underlying mechanisms remain unclear. We hypothesized that GA suppresses pain in part by activating supraspinal analgesic circuits. We discovered a distinct population of GABAergic neurons activated by GA in the mouse central amygdala (CeA_GA neurons). In vivo calcium imaging revealed that different GA drugs activate a shared ensemble of CeA_GA neurons. CeA_GA neurons also possess basal activity that mostly reflects animals' internal state rather than external stimuli. Optogenetic activation of CeA_GA potently suppressed both pain-elicited reflexive and self-recuperating behaviors across sensory modalities and abolished neuropathic pain-induced mechanical (hyper-)sensitivity. Conversely, inhibition of CeA_GA activity exacerbated pain, produced strong aversion and canceled the analgesic effect of low-dose ketamine. CeA_GA neurons have widespread inhibitory projections to many affective pain-processing centers. Our study points to CeA_GA as a potential powerful therapeutic target for alleviating chronic pain.