The dual role of the orexin/hypocretin system in modulating wakefulness and respiratory drive Christian Gestreau, Michelle Be ´vengut and Mathias Dutschmann Introduction The excitatory neuropeptide orexin (or hypocretin) is synthesized by neurons restricted to the lateral hypo- thalamus [1,2]. Only two splice orexin variants (OXA and OXB) derived from a unique precursor [1] have been identified, which bind two G-protein-coupled receptors (OX 1 R and OX 2 R) [2]. Orexin neuron projections target a large number of forebrain, limbic, and brainstem nuclei [3,4,5  ] and, in turn, they receive inputs from numerous brain nuclei that govern interoceptive and homeostatic signals [4,6]. Thus, the physiological role of orexin neurons is heterogeneous because of the complexity of their anatomical connections. Indeed, orexin signaling is involved in the regulation of many neuronal circuits; the most prominent ones control feeding and energy homeostasis [7,8  ,9] as well as sleep–wake states [7,10,11,12  ,13  ]. Orexin signaling has also been implicated in stress [14,15] and reward [16] responses, and as regulator of autonomous processes such as emotion and cardiorespiratory functions [9,17,18]. In rodents, canines, and humans, orexin deficiency is associated with narcolepsy characterized by sleep attacks and sleep fragmentation [19–21]. The present review is largely dedicated to the implications of orexin in the sleep–wake state-dependent regulation of breathing and the potential role this neurotransmitter may play in patients with certain obstructive sleep apnea syn- dromes (OSAS). Orexins control sleep and wake states The sleep–wake cycle of mammals is largely controlled by neural populations located in the hypothalamus and CRN2M, CNRS, Department of Neurovegetative Physiology, University of Aix-Marseille (II – III), Marseille, France Correspondence to Dr Christian Gestreau, PhD, CRN2M, CNRS-UMR6231, University Paul Ce ´ zanne, MP3-Respiration, case 362, Avenue Escadrille Normandie-Niemen, 13397 Marseille, France Tel: +33 0 491288451; e-mail: christian.gestreau@univ-cezanne.fr Current Opinion in Pulmonary Medicine 2008, 14:512–518 Purpose of review Today, numerous studies show that orexin peptides act as regulators of many functions including the control of sleep–wake states, breathing, and central chemosensitivity. However, little is known on neuronal mechanisms by which orexin regulates breathing in a state-dependent manner. This review summarizes recent data on the control of neuronal circuits by orexin, with a special emphasis on breathing, central chemosensitivity, and obstructive sleep apneas. Recent findings Activity of hypothalamic orexinergic neurons is subjected to maturation and is mandatory to maintain long bouts of wakefulness in adults. At wake onset, this activity progressively builds up as a result of synaptic interactions and reinforces the awake state. Orexin deficiency attenuates the hypercapnic reflex only during wakefulness and is correlated with an increase in sleep apneas. Intrinsic sensitivity to CO 2 /pH of orexin neurons may impact on brainstem chemosensitive neurons, and this effect likely involves TWIK (tandem of P domains in a weak inwardly rectifying K þ channel)-related acid sensitive K þ (TASK)-like potassium currents. Summary Orexin signaling is directly involved in the control of upper airway patency in particular during wakefulness, whereas decreasing activity of orexinergic neurons may contribute to upper airway collapse during sleep causing obstructive sleep apnea. Future research should focus on the role of orexin in upper airway control, which may lead to new clinical strategies for treating breathing disorders associated with sleep. Keywords brainstem networks, breathing, sleep apnea, upper airways, vigilance states Curr Opin Pulm Med 14:512–518 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins 1070-5287 1070-5287 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MCP.0b013e32831311d3