Norepinephrine neurons in the nucleus of the solitary tract mediate allodynia related to systemic inflammation in mice

In response to peripheral inflammation, such as the intraperitoneal administration of lipopolysaccharide (LPS), inflammatory cytokines recruit afferent neurons that communicate the inflammation to the brain and, in addition, cytokines are released to the bloodstream and reach circumventricular organs in the brain, such as the area postrema (AP). The nucleus of the solitary tract (NTS) perceives peripheral inflammatory stimuli both directly from afferent peripheral nerves and indirectly through its bidirectional connection to the AP. Norepinephrine (NE) neurons within the NTS are known to mediate behavioral and physiological responses to stress, especially stress related to inflammatory challenges in the periphery. However, the limitations of traditional pain assays limit the understanding of the influence of NTS NE neurons on pain. Here, we used the Blackbox, a machine-learning assisted behavioral analysis apparatus that was developed specifically for the study of pain in rodents. First, we determined the Blackbox variables that correlate to allodynia in mice submitted to intraperitoneal injection of LPS. IP injection of LPS caused several changes to behavior and posture. Most notably, the distance travelled, hind paw toe spread and hind paw distance significantly decreased in response to LPS and strongly correlated with decreased von Frey mechanosensitivity threshold. Selective chemogenetic activation of NTS NE neurons caused similar pain-related behaviors, while inhibition of NTS NE neurons partially reversed the impact of LPS on pain-related behaviors. Taken together, these data show that the NE neurons within the NTS mediate allodynia in response to peripheral inflammation, contributing to the nociception aspect of sickness behaviors.