Orexin, also known as hypocretin, is a neurotransmitter in the brain that regulates various bodily functions. Orexin receptors are specialized proteins on brain cells that bind to orexin, facilitating its effects. Their discovery in 1998 by two independent research groups significantly advanced neuroscience, revolutionizing the understanding of sleep and wakefulness regulation.
The Role of Orexin Receptors in the Body
Orexin receptors play a role in regulating wakefulness and alertness. Orexin neurons, located in the lateral hypothalamus, project widely throughout the central nervous system, influencing various brain nuclei involved in arousal, such as the serotonergic dorsal raphe nucleus, noradrenergic locus coeruleus, and histaminergic tuberomammillary nucleus. Orexin signaling promotes stable wakefulness and can suppress rapid eye movement (REM) sleep.
Beyond sleep regulation, orexin receptors also influence appetite and energy expenditure. Orexin stimulates food intake by increasing the frequency and duration of meals, and it can delay the onset of satiety. This system activates when the body experiences nutritional depletion, prompting food seeking while maintaining alertness. Orexin also increases energy expenditure by activating brown adipose tissue, which generates heat and contributes to body weight regulation.
Orexin receptors are also involved in the body’s response to stress. Orexin neurons activate with acute stressors, projecting to brain regions that coordinate the hypothalamic-pituitary-adrenal (HPA) axis, the body’s central stress response system. Increased orexin signaling can contribute to heightened arousal and anxiety, a characteristic seen in some stress-related disorders. The specific contributions of the two orexin receptor subtypes, OX1R and OX2R, to stress responses are still being investigated, with OX2R appearing to play a role in HPA axis activation.
The brain’s reward system is another area influenced by orexin receptors. Orexin neurons project to areas like the ventral tegmental area (VTA) and the nucleus accumbens, which are associated with motivated and reward-seeking behaviors. Orexin signaling can promote drug-induced changes in the VTA, suggesting a role in addiction and relapse.
Orexin Receptors and Sleep Disorders
When the orexin system malfunctions, it can lead to various sleep-wake disturbances. Narcolepsy Type 1, previously known as narcolepsy with cataplexy, is strongly linked to a deficiency of orexin. This disorder is characterized by excessive daytime sleepiness and sudden episodes of muscle weakness, called cataplexy. The loss of orexin-producing neurons in the hypothalamus is believed to be the underlying cause, often due to an autoimmune attack.
The reduced levels of orexin in individuals with Narcolepsy Type 1 lead to an inability to maintain stable wakefulness and a disinhibition of REM sleep, causing intrusions of REM sleep events into wakefulness, such as sleep paralysis and hypnagogic hallucinations. While the direct link is strongest with Narcolepsy Type 1, imbalances in the orexin system might also contribute to other sleep disturbances like insomnia. Hyperactivity of the orexin system, which promotes arousal, can contribute to insomnia, characterized by difficulty falling or staying asleep.
Targeting Orexin Receptors for Treatment
Understanding orexin receptors has opened new avenues for therapeutic interventions. Orexin receptor antagonists, drugs that block orexin from binding to its receptors, have been developed to treat insomnia. These medications work by inhibiting the wake-promoting signals normally mediated by orexin, thereby helping to induce sleep. Examples of these dual orexin receptor antagonists (DORAs) include suvorexant (Belsomra), lemborexant (Dayvigo), and daridorexant (Quviviq).
These antagonists offer a different mechanism of action compared to traditional sleep aids like benzodiazepines, as they do not directly modulate gamma-aminobutyric acid (GABA) receptors. This class of drugs generally shows a low potential for dependence or withdrawal symptoms.
Ongoing research explores the potential of orexin receptor agonists, which activate orexin receptors, as a future treatment for conditions like narcolepsy or excessive daytime sleepiness. These experimental drugs, such as ALKS 2680 and danavorexton, aim to restore orexin signaling, particularly targeting the OX2 receptor which plays a major role in maintaining wakefulness. While still in developmental stages, these agonists show promise in preclinical and early clinical trials for improving wakefulness and reducing cataplexy in narcolepsy models.