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Hypocretin in Narcolepsy and How It Affects Sleep

Posted on August 03, 2021
Medically reviewed by
Allen J. Blaivas, D.O.
Article written by
Brooke Dulka, Ph.D.

Narcolepsy is a sleep disorder that affects roughly one in every 2,000 people. The most common symptoms of narcolepsy are excessive daytime sleepiness, sleep paralysis, and cataplexy (sudden, temporary loss of muscle tone). Although the condition still isn't well understood by many physicians, science has begun to unravel the potential causes of this neurological (brain) disorder. Much of this research points toward a brain hormone known as hypocretin (orexin). Hypocretin affects sleep and plays a critical role in narcolepsy.

What Is Narcolepsy?

There are two types of narcolepsy: narcolepsy with cataplexy (type 1 narcolepsy) and narcolepsy without cataplexy (type 2 narcolepsy). The core signs and symptoms of narcolepsy include:

  • Excessive daytime sleepiness
  • Falling asleep unexpectedly
  • Fatigue and decreased alertness
  • Sleep paralysis (the inability to move while falling asleep or while waking up)
  • Abnormal sleep cycles and rapid eye movement (REM) sleep patterns
  • Hypnagogic hallucinations (hallucinations that occur while falling asleep)
  • Hypnopompic hallucinations (hallucinations that occur while waking)
  • Cataplexy (sudden muscle weakness triggered by emotional states; occurs only in type 1 narcolepsy)

What causes these signs and symptoms? For many researchers, the evidence points toward hypocretin.

What Is Hypocretin?

Hypocretin is a brain hormone or neuropeptide. In the brain, it plays an important role in regulating sleep and arousal states, as well as food intake. There are two forms of hypocretin: hypocretin-1 (orexin-A) and hypocretin-2 (orexin-B). Hypocretin-1 is the form of hypocretin that is generally associated with narcolepsy.

Like other neurochemicals in the brain, these chemical messengers have specific receptor sites where they fit, like locks in a key, to perform their actions in the brain. There are two types of hypocretin receptors. The type 1 hypocretin receptor responds preferentially to hypocretin-1, and the type 2 hypocretin receptor will respond to both forms of the hypocretin peptides. Based on how the receptor types are distributed inside the brain, particularly the hypothalamus (area of the brain that controls functions like hunger, thirst, sleep, and emotions), researchers believe that both types of receptors likely play a role in sleep processes. For instance, around the time that hypocretin was discovered, mutations in the type 2 receptor were implicated in canine narcolepsy.

Although there is a clear association between the hypocretin system and narcolepsy, hypocretin is also critical for sleeping normally.

How Does Hypocretin Affect Sleep Normally?

Hypocretin is thought to play a critical role as a “flip-flop” switch in the brain for sleep-wake transitions. Research in animals has demonstrated that hypocretin neurons (brain cells) in the lateral portion of the hypothalamus send signals to the locus coeruleus, another area of the brain involved in sleep. Activity in this pathway initiated by hypocretin acts as the switch between states of sleep and wakefulness. Appropriate sleep cycles and transitions to wakefulness are essential components of healthy sleep. When these sleep cycles begin to break down, a diagnosis of a sleep disorder such as narcolepsy may be made.

Hypocretin and Narcolepsy

All individuals with narcolepsy have deficits in the hypocretin system, although people who have narcolepsy type 2 have a less severe deficit in hypocretin-1 compared to those with type 1. In sleep studies, people with narcolepsy displayed a higher frequency of sleep-wake transitions, as well as an abnormal number of transitions to and from REM sleep. Furthermore, a greater number of sleep state transitions were associated with lower levels of hypocretin-1 in these same individuals.

It is widely believed that narcolepsy results from a loss of hypocretin neurons in the hypothalamus. This loss may, in part, have an autoimmune component. In other words, the immune system may be attacking the brain, causing hypocretin nerve cells to die and, in a way, breaking the flip-flop switch that regulates sleep transitions in the human brain.

The hypocretin system is also governed by underlying genetic processes. In one study, scientists removed the gene responsible for producing hypocretin in mice, and these animals developed symptoms similar to those observed in individuals with narcolepsy — including dysregulated sleep patterns and narcoleptic attacks. Further supporting the autoimmune hypothesis of narcolepsy, in one study, nearly all people with NT1 were found to carry the human leukocyte antigen (HLA) allele HLA-DQB1*06:02, as well as another variant known as the HLA-DQA1*0102 allele.

Overall, hypocretin-1 is dysregulated in individuals with narcolepsy. However, understanding the important role that hypocretin plays in the pathogenesis of narcolepsy may help inform future treatment options, as advances in gene therapy and drug discovery are made.

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References
  1. Narcolepsy — National Organization of Rare Disorders
  2. Delayed Diagnosis of Narcolepsy: Characterization and Impact — Sleep Medicine
  3. Hypocretin (Orexin) Deficiency in Human Narcolepsy — The Lancet
  4. Prevalence and Incidence of Narcolepsy in a U.S. Health Care Claims Database, 2008-2010 — Sleep
  5. Narcolepsy — Mayo Clinic
  6. The Hypocretin/Orexin Ligand-Receptor System: Implications for Sleep and Sleep Disorders — Trends in Neuroscience
  7. Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors That Regulate Feeding Behavior — Cell
  8. The Role of Cerebrospinal Fluid Hypocretin Measurement in the Diagnosis of Narcolepsy and Other Hypersomnias — Archives of Neurology
  9. The Hypocretin/Orexin System — Journal of the Royal Society of Medicine
  10. Distribution of Orexin Receptor mRNA in the Rat Brain — FEBS Letters
  11. The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene — Cell
  12. Mechanism for Hypocretin-Mediated Sleep-to-Wake Transitions — PNAS
  13. What Is Sleep and Why Is It Important? — American Sleep Association
  14. Predictors of Hypocretin (Orexin) Deficiency in Narcolepsy Without Cataplexy — Sleep
  15. The Neurobiological Basis of Narcolepsy — Nature Reviews Neuroscience
  16. The Autoimmune Basis of Narcolepsy — Current Opinion in Neurobiology
  17. Narcolepsy in Orexin Knockout Mice: Molecular Genetics of Sleep Regulation — Cell
  18. Complex HLA-DR and -DQ Interactions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups — American Journal of Human Genetics
  19. An Overview of Hypocretin Based Therapy in Narcolepsy — Expert Opinion on Investigational Drugs
All updates must be accompanied by text or a picture.
Allen J. Blaivas, D.O. is certified by the American Board of Internal Medicine in Critical Care Medicine, Pulmonary Disease, and Sleep Medicine. Review provided by VeriMed Healthcare Network. Learn more about him here.
Brooke Dulka, Ph.D. is a freelance science writer and editor. She received her doctoral training in biological psychology at the University of Tennessee. Learn more about her here.

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