Orexin/hypocretin system and autonomic control

Orexins (OX-A and OX-B), also referred to as hypocretin 1 and 2, are neuropeptides synthesized by neurons located in the perifornical and lateral regions of the hypothalamus. Orexin neurons have extensive connections with the prefrontal cortex, limbic structures, hypothalamus, and brainstem, including areas involved in control of arousal, reward mechanisms, and autonomic control, and exert a primarily excitatory effect on neuronal activity via OX₁ and OX₂ receptors. The functions of the orexin system have been investigated using pharmacologic approaches and, more recently, knockout models. Since their discovery in 1998,^1,2 orexins have been linked to multiple physiologic functions such as arousal, energy homeostasis, feeding, thermoregulation, and neuroendocrine and cardiovascular control, which are associated with or mediated by changes in the autonomic nervous system. The progress of knowledge in this area has been fueled by comparative approaches on different species, which show substantial similarities in basic biology of the orexin system. Loss of orexin signaling is associated with narcolepsy with cataplexy (NC) in both animal models and humans. Patients with NC have changes in body weight and cardiovascular function that may predispose to cardiovascular morbidity. However, the contribution of loss of orexin signaling in these manifestations is incompletely understood. The organization and multiple functions of the orexin system have been the subjects of recent comprehensive reviews.^3–6 The present review focuses on the role of the orexin system in autonomic control and its potential implications in human NC.