Midbrain somatostatin-expressing cells control pain-suppression during defensive states

In threatening situations, animals exhibit a broad range of behavioral and autonomic responses. As such, a crucial adaptive response is the inhibition of pain, which facilitates relevant defensive behaviors that promote survival. Whereas the structures and mechanisms involved in fear and pain behaviors are well documented, little is known about the precise neuronal mechanisms mediating the emotional regulation of endogenous pain-suppression. Here, we used a combination of behavioral, anatomical, optogenetic, and electrophysiological approaches to investigate, in male mice, the role of somatostatin-expressing cells in the ventrolateral periaqueductal gray matter (SST⁺ vlPAG cells) in the control of analgesia induced during defensive states. Our data indicate that optogenetic inhibition of SST⁺ vlPAG cells promotes analgesia irrespective of animal defensive state. In contrast, optogenetic activation of long-range SST⁺ vlPAG cells that project to the rostral ventromedial medulla (RVM) abolishes the analgesia mediated by fear behavior. Together, these results identify a novel circuit mechanism composed of long-range SST⁺ vlPAG cells projecting to the RVM that regulate analgesia elicited during defensive states.