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Orexin
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Orexins, also called hypocretins, are the common names given to a pair of highly excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains.
The two related peptides (Orexin-A and B, or hypocretin-1 and -2), with approximately 50% sequence identity, are produced by cleavage of a single precursor protein. Orexin-A/hypocretin-1 is 33 amino acid residues long and has two intrachain disulfide bonds, while Orexin-B/hypocretin-2 is a linear 28 amino acid residue peptide.
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Encyclopedia
Orexins, also called hypocretins, are the common names given to a pair of highly excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains.
The two related peptides (Orexin-A and B, or hypocretin-1 and -2), with approximately 50% sequence identity, are produced by cleavage of a single precursor protein. Orexin-A/hypocretin-1 is 33 amino acid residues long and has two intrachain disulfide bonds, while Orexin-B/hypocretin-2 is a linear 28 amino acid residue peptide. Studies suggest that orexin A/hypocretin-1 may be of greater biological importance than orexin B/hypocretin-2. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain. The orexin peptides bind to the orexin receptor, a G-protein coupled receptor.
The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates. The peptides are thought to have arisen early in vertebrate evolution.
Functions
The orexin/hypocretin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin A/hypocretin-1 increases food intake. In addition, it stimulates wakefulness and energy expenditure.
Wakefulness
Orexin seems to promote wakefulness.
The discovery that orexin/hypocretin dysregulation causes the sleep disorder narcolepsy in mice subsequently indicated a major role for this system in sleep regulation. Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy (loss of muscle tone in response to strong, usually positive, emotions). Dogs that lack a functional receptor for orexin/hypocretin have narcolepsy, while animals and people lacking the orexin/hypocretin neuropeptide itself also have narcolepsy. Orexin/hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems and appear to play an important role in stabilizing wakefulness and sleep.
Recent studies indicate that a major role of the orexin/hypocretin system is to integrate metabolic, circadian and sleep debt influences to determine whether the animal should be asleep or awake and active. Central administration of orexin A/hypocretin-1 strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin A/hypocretin-1 transmission. The orexin/hypocretin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin/hypocretin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin/hypocretin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30-36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.
Recently, transgenic mice have been engineered to lack the gene for orexin. Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. Researchers are using this animal model of narcolepsy to study the disease.
Food intake
Orexin increases the craving for food, and correlates with the function of the substances that promote its production.
Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.
Hypocretin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin/hypocretin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation. Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis.
Pharmacologic potential
The research on orexin/hypocretin is still in an early phase, although many scientists believe that orexin/hypocretin-based drugs could help narcoleptics and increase alertness in the brain without the side effects of amphetamines.
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism. Lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.
A study has reported that transplantation of orexin/hypocretin neurons into the pontine reticular formation in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.
Because hypocretin-1 receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats. By blocking the hypocretin-1 receptor with low doses of the selective antagonist SB-334,867, nicotine self-administration decreased and also the motivation to seek and obtain the drug. The study showed that blocking of receptors in insula decreased self-administration, but not blocking of receptors in the adjacent somatosensory cortex. The greatest decrease in self-administration was though found when blocking all hypocretin-1 receptors in the brain as a whole. A rationale for this study was the fact that insula has been implicated in regulating feelings of craving. Insula contains hypocretin-1 receptors. It has been reported that smokers who sustained damage to the insula lost the desire to smoke.
History and nomenclature
Masashi Yanagisawa and colleagues at the University of Texas Southwestern Medical Center at Dallas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these hormones.
Luis de Lecea, Thomas Kilduff, and colleagues also reported discovery of these same peptides, dubbing them hypocretins to indicate that they are synthesized in the hypothalamus and to reflect their structural similarity to the hormone secretin [(i.e., hypothalamic secretin).
The name of this family of peptides is currently in dispute. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial (i.e., hypocretin induced subjects eat more because they are awake more), while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions, and that waking is one of the important factors that supports feeding behavior. Both "orexin" and "hypocretin" will likely continue to appear in published works until a preferred name has been accepted by the scientific community.
Selective Ligands
Several drugs acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia. No non-peptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray. Several non-peptide antagonists are in development however; SB-649,868 is under development by GlaxoSmithKline for sleep disorders and is an orexin receptor antagonist. Another OX1 and OX2 receptor antagonist (ACT-078573, almorexant) is a similar compound under development for primary insomnia by Actelion.
Most ligands acting on the orexin system so far are polypeptides modified from the endogenous agonists Orexin-A and Orexin-B, however there are some subtype-selective non-peptide antagonists available for research purposes.
- SB-334,867 - selective OX1 antagonist, N-(2-Methyl-6-benzoxazolyl)-N"-1,5-naphthyridin-4-yl urea, CAS# 249889-64-3
- SB-408,124 - selective OX1 antagonist, orally active, N-(6,8-Difluoro-2-methyl-4-quinolinyl)-N'-[4-(dimethyla mino)phenyl]urea, CAS# 288150-92-5
See also
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