A central amygdala-locus coeruleus pathway mediating pain under chronic stress

Chronic stress can induce pain and drive development of aversion, although the specific neural circuits that contribute to encoding such behavioral responses remain unclear. Here, we find that noradrenergic neurons in locus coeruleus (NE^LC) regulate the formation of allodynia and aversion under chronic restraint stress in mice, driven by enhanced activity of NE^LC-projecting GABAergic neurons in the central amygdala (CeA). Selectively inhibiting this GABAergic CeA→LC pathway significantly alleviates pain sensitization and aversion behaviors, but without impacting chronic stress-associated depression-like behaviors. Additionally, these NE^LC neurons receiving inputs from CeA monosynaptically activate glutamatergic neurons in the lateral periaqueductal gray (Glu^LPAG) to mediate pain sensitization and aversion. This study thus defines a specific CeA→LC→LPAG pathway through which chronic stress leads to pain and aversion, without affecting depression-like behaviors, expanding our fundamental understanding of the circuit basis for stress-related pain.