Upon threatening situations, animals exhibit a broad range of behavioral and autonomic responses necessary for survival. Under such conditions, a crucial adaptive response is the inhibition of pain responses that would otherwise interfere with behavioral defensive responses. Whereas the structures and mechanisms involved in fear and pain behavior 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 show that somatostatin-expressing cells in the ventrolateral periaqueductal gray matter (SST+ vlPAG cells) control the analgesia induced by a negative emotional state. Our data indicate that the optogenetic inhibition of SST+ vlPAG cells promotes analgesia. Conversely, the optogenetic activation of long-range SST+ vlPAG cells that project to the RVM abolishes the analgesia mediated by a negative emotional state without impacting fear behavior. Together these results identify a novel brainstem circuit mechanism composed of long-range SST+ vlPAG cells projecting to the RVM that regulate analgesia elicited by negative emotional states.