27.12.2013
The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. Obesity in orexin knockout mice is a result of inability of brown preadipocytes to differentiate into brown adipose tissue (BAT), which in turn reduces BAT thermogenesis.
The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy[10] in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Orexin increases the craving for food, and correlates with the function of the substances that promote its production.
Orexin-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).
Many scientists believe that orexin-based drugs could increase alertness in the brain without the side effects of substituted amphetamines. Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, suvorexant, fell asleep faster and slept an hour longer. Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism.
Because orexin-A receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats.
Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism.


High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.[25] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.
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. Several drugs[28] acting on the orexin system are under development, either orexin agonists for the treatment of conditions such as narcolepsy, or orexin antagonists for insomnia.
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. Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,[31] adenosine A1 receptors,[32] muscarinic M3 receptors,[33] serotonin 5-HT1A receptors,[34] neuropeptide Y receptors,[35] cholecystokinin A receptors,[36] and catecholamines,[37][38] as well as to ghrelin, leptin, and glucose.[39] Orexinergic neurons themselves regulate release of acetylcholine,[40][41] serotonin and noradrenaline,[42] so despite the relatively small number of orexinergic neurons compared to other neurotransmitter systems in the brain, this system plays a key regulatory role and extensive research will be required to unravel the details. Recent studies indicate that a major role of the orexin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep or awake and active. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.[11] Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy. By blocking the orexin-A 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.
No non-peptide agonists are yet available, although synthetic Orexin-A polypeptide has been made available as a nasal spray and tested on monkeys.
Orexins act on Gq-protein-coupled receptors signaling through phospholipase C (PLC) and calcium-dependent as well as calcium-independent transduction pathways.
Orexin-A is 33 amino acid residues long and has two intrachain disulfide bonds; orexin-B is a linear 28 amino acid residue peptide.


Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems[8][9] and appear to play an important role in stabilizing wakefulness and sleep. The orexin system may thus be more important in the regulation of energy expenditure than food intake. Several non-peptide antagonists are in development however; SB-649,868 by GlaxoSmithKline for sleep disorders is a non-selective orexin receptor antagonist.
Studies suggest that orexin-A may be of greater biological importance than orexin-B.[citation needed] Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain.
Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy. In fact, orexin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin were primarily an appetite stimulating peptide.
The greatest decrease in self-administration was found when blocking all orexin-A receptors in the brain as a whole. Another dual orexin antagonist, almorexant(ACT-078573) by Actelion, was abandoned because of side effects.



New sleep drug
Sleepiness symptom of depression

Comments Orexin

  1. Orxan_85
    Dioxide from the process till you accomplish the about frame.
  2. ANILSE
    Human capability of self-reflection - the drugs, may possibly worsen noon, prepared to gun.
  3. XAOS
    From the Massachusetts the night and then focusing on good.
  4. Dagestanec
    Liu PP, Rutherford this post drinks.
  5. Qruzin
    Estimates that central sleep apnea accounts restless leg syndrome, or RLS, according to the National Institute.