| Orexin (hypocretin) refers to a small family of hypothalamic neuropeptides produced from a single precursor (prepro-orexin) that is proteolytically processed into orexin-A and orexin-B, which act as high-affinity ligands for two rhodopsin-like G protein-coupled receptors, OX1R and OX2R, to coordinate arousal, energy balance, and motivated behaviors. Orexin neurons are clustered in the lateral and posterior hypothalamus and send dense projections throughout the brainstem and forebrain, including to monoaminergic and cholinergic arousal nuclei, the cortex, limbic regions, and autonomic centers, creating a widely distributed output network through which orexin peptides tonically stabilize wakefulness and phasic arousal by exciting noradrenergic, dopaminergic, histaminergic, and cholinergic systems. At the structural and receptor level, orexin-A and orexin-B share an N-terminal region and C-terminal amidation but differ in length and disulfide bonding, features that influence receptor selectivity, with OX1R showing preference for orexin-A and OX2R binding both peptides more equivalently; both receptors couple promiscuously to Gq, Gi/o, and Gs families in a cell-type–dependent manner, and robustly activate phospholipase cascades (PLC, PLA2, PLD) leading to IP3/Ca²⁺ mobilization, diacylglycerol and arachidonic acid production, and in some contexts diacylglycerol lipase–mediated synthesis of the endocannabinoid 2-arachidonoylglycerol that feeds back onto CB1 receptors. In central neurons, these signaling events converge on ion channels and exchangers, with inhibition of leak K⁺ currents and activation of the Na⁺/Ca²⁺ exchanger and nonselective cation channels producing strong depolarization and increased firing, a mechanism that underlies orexin-mediated excitation of wake-promoting nuclei, hypothalamic feeding circuits, and reward pathways. Orexin neurons integrate multiple afferent signals related to energy status (glucose, leptin, ghrelin), circadian phase, and stress, and adjust peptide output accordingly; elevated orexin signaling promotes wakefulness, physical activity, and food seeking, while loss of orexin or OX2R function causes narcolepsy with cataplexy in humans and animal models, directly linking orexin tone to sleep–wake stability. Beyond sleep and feeding, orexinergic projections to the hippocampus, amygdala, and prefrontal cortex modulate synaptic plasticity and memory processes, and receptor-specific pharmacology and mapping studies indicate that OX1R pathways have prominent roles in anxiety, pain modulation, and drug reward, whereas OX2R is particularly critical for non-REM and REM sleep regulation, making receptor subtype engagement an important determinant of functional output. Dysregulation of orexin signaling contributes to several disease contexts: deficiency or autoimmune loss of orexin neurons in narcolepsy; altered orexin and receptor expression patterns in obesity, addiction, depression, and neurodegenerative conditions; and aberrant orexin receptor activity in some cancers where orexin can induce caspase-dependent apoptosis. |
