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Orexin - Wikipedia, the free encyclopedia

Orexin - Wikipedia, the free encyclopedia

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. The discovery that orexin/hypocretin dysregulation causes the sleep disorder narcolepsy[1] 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.

Problems with Dopamine, norepinephrine and acetylcholine are related to ADD.

Recent studies indicate that a major role of the orexin/hypocretin system may be 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.

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.

Orexin/hypocretin-producing cells have recently been shown to be inhibited by leptin (by leptin receptors) but are activated by ghrelin and hypoglycemia. Orexin/hypocretin may therefore 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.

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.

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