<p>Hospitalization in an intensive care unit (ICU) can be associated with a perilous functional decline. Patients can develop impairments in mobility, cognition, and ability to perform daily living activity. Immobility due to prolonged bed rest in the ICU play a major role in the development of ICU-acquired weakness. However, there has been no pharmacotherapy which promotes early mobilization of patients. Recently, we found peripherally administered orexin rescues mice with endotoxin shock. Furthermore, our group developed non-peptide orexin-2 receptor selective agonist, YNT-185, which can go through the blood-brain barrier. The purpose of this study is to examine whether an orexin agonist could improve inflammation-induced immobility in mice. </p><p>We found that intraperitoneal administration of YNT-185 accelerates horizontal activity and wheel running after LPS challenge in wild type mice, but not in in orexin receptor knockout mice. This effect is mimicked by ICV injection of orexin, or overexpression of orexin in mice.</p><p>Immunohistochemical experiments using anti-Fos antibody suggested that serotonergic neurons in the medullary raphe nuclei are activated after administration of YNT-185 in LPS-challenged mice. We found that these neurons send projections to the ventral tegmental area, nucleus of the solitary tract, and the rostral ventrolateral medulla, regions involved in the regulation inflammation. We hypothesized that orexin accelerate recovery from inflammation by activating the reward system and modulating the autonomic nervous system through the medullary raphe nuclei. </p><p>We are now investigating the neural mechanism of the effects on inflammation-induced immobility by manipulation of serotonergic neurons in the medullary raphe nuclei.</p>