The Orexinergic System: Neurobiology and Clinical Implications

Orexins, also known as hypocretins, are neuropeptides that play a crucial role in regulating various physiological processes, including sleep–wake cycles, energy homeostasis, and arousal. Orexins are neuropeptides selectively produced by a group of neurons located in the dorsolateral part of the hypothalamus.[1] In 1998, two independent research groups exploring novel signaling molecules discovered orexin neuropeptides and their receptors. The peptides were named orexin-A and B by Sakurai et al.,[1] with the belief that they played a role in promoting feeding (the term "orexin" derived from the Greek word "orexis," meaning appetite). At the same time, Sutcliffe and de Lecea[2] designated the peptides as hypocretin-1 and 2 due to their production in the hypothalamus and certain similarities to the incretin family of peptides. As the years passed, further research showed that orexin peptides have their main effect in the arousal and sleep system, while also having minor effects on feeding and appetite. The disease, in which there is loss of orexin-producing neurons is called narcolepsy. This is one of the most common causes of daytime sleepiness. This discovery prompted interest in the development of orexin antagonists as a novel approach to promote sleep and treat insomnia.[3] We know now that these peptides have diverse functions, including the regulation of the sleep–wake cycle,[4] control of energy homeostasis,[5] modulation of neuroendocrine activities,[6] impact on glucose metabolism,[7] (Tsuneki et al., 2010), involvement in stress-adaptive responses,[8] and influence on reward-seeking behavior and drug addiction.[9] Orexins exert their effects by binding to their specific G-protein-coupled receptors (GPCRs), namely orexin receptor type 1 (OX1R, also known as Hcrtr-1) and type 2 (OX2R, or Hcrtr-2). These receptors activate distinct downstream signaling pathways and hence contribute to a diverse array of physiological functions.[10] OREXINS AND OREXIN RECEPTORS Orexins are produced by a group of neurons situated in the dorsolateral region of the hypothalamus. Orexins have two forms – orexin A and B, comprising 33 and 28 amino acids, respectively, and sharing a 64% similarity in their amino acid sequences. Orexins bind to GPCRs known as OX1 and OX2 orexin receptors. The OX2 receptors have equal affinity for both orexin A and B. In contrast, OX1 receptors have a tenfold higher affinity for orexin-A compared to orexin-B.[11] OREXINERGIC SYSTEM AND ITS NEURAL CONNECTIONS Studies have shown that neurons expressing orexin peptides are confined to a minute area within the central nervous system. Specifically, these neurons are predominantly situated in the perifornical region and the lateral hypothalamus, particularly at the tuberal level of the hypothalamus where the median eminence is observable. This region of the lateral hypothalamus is involved in a diverse range of behavioral and homeostatic regulatory systems. The presence of orexin-expressing neurons in this location has generated hypotheses regarding their physiological significance.[12,13] INPUTS TO OREXIN NEURONS Hypothalamus: Orexin neurons receive projections from the hypothalamus, particularly from the ventrolateral preoptic nucleus (VLPO), involved in sleep control, and the suprachiasmatic nucleus, which houses the master circadian clock[14] Basal Forebrain: Connections from the basal forebrain contribute to orexin neuron activity[15] Amygdala: The amygdala, involved in emotion and memory, also projects to orexin neurons[16] Brainstem: Orexin neurons receive inputs from the brainstem, a region essential for various autonomic and motor functions.[17] OUTPUTS FROM OREXIN NEURONS VLPO: Orexin neurons project back to the VLPO, influencing sleep control[18] Tuberomammillary nucleus (TMN): Orexin neurons project to TMN in the hypothalamus, contributing to sleep regulation[19] Locus coeruleus (LC): Orexin neurons send projections to LC in the pons, impacting sleep control[20] Arcuate nucleus (ARC): Orexin neurons project to the ARC in the hypothalamus, involved in feeding control[21] Ventral tegmental area (VTA): Orexin neurons project to the midbrain VTA, relevant to motivation and reward.[22] Distribution in pons and medulla Orexin fibers are distributed through the raphe nuclei and the reticular formation in the pons and medulla. These areas are relevant to sleep and motor control.[23] Autonomic control Orexin neurons project to structures of the central autonomic network. Its targets include the rostral ventrolateral medulla and the hypothalamic paraventricular nucleus. These structures are involved in sympathetic and parasympathetic control.[24] Receptor expression Different structures express orexin receptors (OX1R and OX2R) to varying extents. For example, VLPO, TMN, and LC neurons mostly express OX2R, OX2R, and OX1R, respectively.[25] To summarize, orexin neurons function as central regulators, integrating signals from various brain regions to modulate essential functions such as sleep, feeding, motivation, and autonomic control. This complicated and diverse network shows the widespread influence of orexin on various physiological processes. OREXINS AND SLEEP The orexin system is essential in the regulation of sleep, wakefulness, and arousal in the central nervous system. Orexins promote wakefulness, and their absence leads to narcolepsy-like symptoms in rodents. Human narcoleptics lack orexin neurons. Central orexin administration induces wakefulness and alleviates narcoleptic symptoms in mice which lack orexin neurons. Orexin neurons project to the cerebral cortex and specific regions implicated in arousal, such as the basal forebrain and the dorsal raphe nucleus. They stimulate cholinergic neurons in the basal forebrain also serotonergic neurons in the dorsal raphe, contributing to cortical activation and wakefulness.[26] Certain brain regions, such as the LC, laterodorsal tegmental nucleus, and pedunculopontine tegmental nucleus, express exclusively OX1R mRNA. These regions, which are vital for cortical arousal and REM sleep maintenance, receive dense orexin innervation, leading to neuronal excitation. Conversely, the TMN expresses only OX2R mRNA and is important for maintaining arousal. Orexin function in this region is excitatory, and orexin fibers form synapses on histaminergic neurons. The wakefulness induced by orexin administration relies on an intact histaminergic system.[27] Orexin antagonists have been used as sleep aids, and several reasons support their use in this context. These include the high genetic conservation of orexin neurons among mammals, which means they are a more translatable target. Orexin drugs have a novel mechanism of action, which means fewer serious side effects and no impact on gait, balance, or motor coordination. In addition, the role of OX2R being more significant than OX1R in sleep regulation supports the rationale for using orexin antagonists.[28] Numerous studies have demonstrated that the orexin system is instrumental in sustaining wakefulness. Intraventricular injections of orexins have been shown to lengthen the awake time. Orexin neurons integrate various inputs, including metabolic and circadian signals, and convey them to neuromodulators, thereby regulating the overall sleep–wake transition.[29] In the context of insomnia, both single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) are under investigation. DORAs, which block both OX1R and OX2R, have shown utility in promoting both nonrapid eye movement and rapid eye movement (REM) sleep. They increase REM sleep duration and decrease latency to REM sleep. DORAs, in studies, appear beneficial in insomnia cases with comorbidities such as schizophrenia and Parkinson's disease.[30] OREXINS AND DEMENTIA Emerging research has begun to unveil a potential connection between orexin dysfunction and dementia, particularly Alzheimer's disease (AD). In AD, orexin-producing neurons in the hypothalamus degenerate early in the disease process. This degeneration disrupts the delicate balance of sleep–wake cycles, leading to disturbances in circadian rhythms and sleep quality. Poor sleep quality, in turn, is associated with an increased risk of cognitive decline and dementia progression. Moreover, orexins play a crucial role in modulating neurotransmitter systems involved in memory and cognition, such as acetylcholine, dopamine, and glutamate. Dysfunction in orexin signaling pathways could impair synaptic plasticity, leading to deficits in learning and memory processes characteristic of dementia. Interestingly, some studies suggest that orexin levels may be altered in individuals with dementia even before clinical symptoms manifest, indicating a potential role for orexins as early biomarkers of neurodegeneration.[31] Understanding the intricate interplay between orexin dysfunction and dementia, pathology holds promise for developing novel therapeutic strategies. Targeting orexin signaling pathways could offer avenues for improving sleep quality, enhancing cognitive function, and ultimately mitigating the progression of dementia. Further research into the precise mechanisms underlying orexin's involvement in dementia is essential for developing effective interventions to combat this devastating condition.[32] OREXINS AND ALCOHOL DEPENDENCE Increasing evidence suggests a significant involvement of orexin signaling in alcohol dependence and addiction. Alcohol consumption can disrupt orexin signaling pathways, leading to dysregulation of sleep–wake cycles, and altered reward processing. Chronic alcohol exposure has been shown to decrease orexin levels in certain brain regions, potentially contributing to withdrawal symptoms and the development of tolerance.[33] Conversely, orexins also influence the reinforcing effects of alcohol. Studies indicate that orexin neurons project to brain regions involved in reward and motivation, such as the VTA and nucleus accumbens. The activation of orexin receptors in these regions enhances the rewarding properties of alcohol and promotes alcohol-seeking behavior. Furthermore, orexins play a role in stress responses, which are closely linked to alcohol dependence. Stress-induced activation of orexin neurons can drive alcohol craving and relapse in individuals with a history of alcohol use disorder.[34] OREXINS AND EATING DISORDERS The orexin system is suggested as a potential link between compulsive eating and sleep disturbances in binge eating disorder (BED). This proposal is based on evidence showing that the orexin system adapts significantly to drug abuse, leading to the hypothesis that chronic consumption of palatable foods may similarly increase orexin system activity, causing disrupted sleep patterns. Poor sleep, in turn, worsens BED, creating a cycle of uncontrollable food consumption. There is a translational implication that pharmacotherapies targeting orexin signaling, currently undergoing trials for substance use disorders, might also be useful in managing eating disorders.[35] OREXINERGIC DRUGS - CLINICAL ASPECTS Over the past decade, the discovery of the orexin system's anatomical connections to sleep/wake and reward circuits has had important clinical implications for patients and physicians, leading to the development of orexin receptor antagonists for treating insomnia. The orexin system is one promising therapeutic target due to its role in sleep regulation, drug addiction mechanisms, stress/emotion regulation, energy balance, and arousal. Drug addiction may exacerbate insomnia through a feedback loop involving increased orexin production.[2] Recent research on DORAs and SORAs has spurred numerous trials for innovative insomnia treatments, aiming for long-term efficacy with fewer side effects compared to other hypnotic drugs. DORAs have shown positive effects on total sleep time by enhancing REM sleep without significantly affecting non-REM sleep. However, foolproof data on SORAs' efficacy and safety are still limited, and systematic comparisons among these drugs are scarce.[36] Despite the rapid development of molecules selectively targeting orexin receptors OX1R and OX2R, many of them remain in the preclinical study stage for long periods of time, often exceeding 4–5 years. One example is the molecule SB-334867 (a SORA targeting OX1R), which exhibited promising results in preclinical studies for epilepsy treatment.[37] We know that these studies have primarily generated hypotheses rather than successfully progressing to the development of a viable drug candidate. The idea that pharmacological blockade of the OX1 receptor could be a potential target for treating seizures and associated anxiety disorders has been flouted, but a successful drug candidate has not yet been realized. Similarly, DORAs have been evaluated for the treatment of cluster headaches and migraine. Dysfunctional orexinergic systems were observed in the etiology of these conditions, with lower orexin levels in episodic migraineurs and higher levels in chronic headache patients. Despite this, SORAs and DORAs have primarily contributed to generating hypotheses and conjectures rather than offering established treatment options.[38] CONCLUSIONS Orexin antagonists have shown promise in treating insomnia, especially for shift workers and those with high sympathetic tone. They may be particularly useful for elderly patients, potentially avoiding side effects seen with traditional medications. However, their effectiveness may be limited for insomnia associated with anxiety or pain. Beyond insomnia, these drugs offer the potential in addressing substance abuse and eating disorders by reducing cravings and aiding in withdrawal. Conversely, the development of orexin agonists has the potential to benefit individuals with narcolepsy and daytime sleepiness. While challenges exist in developing small-molecule agonists, allosteric modulators may selectively enhance orexin signaling. Ongoing research on orexin antagonists in animals and humans provides insights into arousal and sleep neurobiology. In the coming years, more information is expected regarding the effectiveness, safety, and specific benefits of these compounds for different insomnia patients. Orexin antagonists, especially DORAs, present a promising avenue for the management of sleep disorders, offering a targeted approach with potential benefits for various patient populations, including those with specific comorbid conditions.