Dayvigo is an orexin receptor antagonist...it blocks neurotransmitters that promote wakefulness.
It isn’t likely to cause rebound insomnia or withdrawal symptoms when stopped...but don’t expect it to fly off shelves.
Dayvigo doesn’t seem to work better than benzos or “Z-drugs”... and it has additional adverse effects and interactions.
For example, Dayvigo can rarely cause transient leg weakness... or sleep paralysis during sleep-wake transitions.
Plus it can cause “sleep driving” and daytime impairment... similar to benzos and Z-drugs.
And watch for interactions, since it’s metabolized by CYP3A4.
Expect Dayvigo to cost about $1.60/dose.
Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.[1] The most common form of narcolepsy, type 1, in which the sufferer experiences brief losses of muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.[2][3]
There are only 10,000–20,000 orexin-producing neurons in the human brain,[2] located predominantly in the perifornical area and lateral hypothalamus.[1][4] They project widely throughout the central nervous system, regulating wakefulness, feeding, and other behaviours.[1] There are two types of orexin peptide and two types of orexin receptor.[5][4]
Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the rat brain.[6][7] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide.[2] Officially, hypocretin (HCRT) is used to refer to the genes and transcripts, while orexin is used to refer to the encoded peptides.[8] There is a high affinity between the orexin system in the rat brain and that in the human brain.[5]
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. In addition, it stimulates wakefulness, regulates energy expenditure, and modulates visceral function.
Wakefulness[edit]
Orexin seems to promote wakefulness. 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. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems[18][19] and appear to play an important role in stabilizing wakefulness and sleep.
The discovery that an orexin receptor mutation causes the sleep disorder canine narcolepsy[20] in Doberman Pinschers subsequently indicated a major role for this system in sleep regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.[21] 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.[22] Narcolepsy results in excessive daytime sleepiness, inability to consolidate wakefulness in the day (and sleep at night), and cataplexy, which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy.
Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than food intake. 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. 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.[23][24]
In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.[25] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.[26] In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.[27]
Food intake[edit]
Orexin increases the craving for food, and correlates with the function of the substances that promote its production. Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback.[28] However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.[29]
Review findings suggest that hyperglycemia that occurs in mice due to a habitual high-fat diet leads to a reduction in signalling by orexin receptor-2, and that orexin receptors may be a future therapeutic target.[30] 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-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, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.[31][32] 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. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.[33]
Addiction[edit]
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of cocaine, opioid, and alcohol addiction.[34][35][36] For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.[37][38]
Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective orexin antagonist SB-334,867 reduced nicotine self-administration in rats and that smokers who suffered damage to the insula, a brain region that regulates cravings and contains orexin-1 receptors, lost the desire to smoke.[39] However, other studies in rats using the dual orexin receptor antagonist TCS 1102 have not found similar effects.[40]
Lipid metabolism[edit]
Orexin-A (OXA) has been recently demonstrated to have a direct effect on an aspect of lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes.[41] The link between OXA and the lipid metabolism is new and currently under more research.
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.[42] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression.
