In the 1990s scientists discovered a previously unknown type of neurotransmitter that influences brain activity. One group of researchers called these chemicals orexins and another, independent group of called them hypocretins. Both names are used in the scientific literature. We prefer Orexin because it is shorter.
Orexins play a part in keeping people awake. Like most of what goes on in the brain related to sleep and waking, there are mysteries and anyone who says they really understand every role that the orexin neurotransmitters play is lying. But we know they are peptides – smallish proteins made in the body. They also interact with other neurotransmitters in ways yet to be untangled, but they unquestionably appear to be involved in arousal and excitation of the brain. The evidence suggests they form a part of the body’s overall sleep-wake regulation system by interacting with GABAergic sleep-promoting neurons and neurotransmitters like histamine, serotonin, melatonin, and acetylcholine. (More here)
The orexin “circuit” consists of the hypothalamic neuropeptides and two types of receptors, referred to in the scientific literature as orexin receptor-1 (OX(1)R) and orexin receptor-2 (OX(2)R). They are also called Orexin A and Orexin B. Receptor 2 has roughly equal affinities for both types of orexins, but receptor 1 has a much greater affinity for receptor 1 (100 to 1000 times) (More here)
Nature has an excellent diagram showing the current understanding of how orexin neurons interact with other areas of the brain: http://www.nature.com/nrn/journal/v8/n3/fig_tab/nrn2092_F3.html
Researchers have found indication that the two receptors (A and B) influence different neuronal pathways and have speculated they play different roles in influencing sleep architecture. Even simple animals have orexins. They have been found to be part of the sleep/wake control system in zebrafish. A mathematical model of sleep physiology shows that even small changes in how orexinergic neurons interact with the rest of the brain have a huge effect on sleep and waking times and the transitions among stages. Further, it is becoming increasingly apparent that the death of orexin neurons is the proximate cause of narcolepsy.
The cells that make orexins are in the hypothalamus part of the brain. This is an evolutionarily old part of the brain, right above the brain stem, and also where the suprachiasmatic nucleus master clock so important in the body’s circadian rhythms is located. It is also where feelings of hunger and satiation seem to originate. Which is why people are interested in orexins and the part they play in body weight To some extent the orexin system is a positive feedback loop, as it appears to be activated by sleep deprivation. Low metabolism, whether caused by low blood sugar or otherwise, stimulates orexin release; perhaps this is evolution’s way to encourage us to wake up and search for food.
Since their relatively recent discovery, orexins have been tied to all sort of physiological phenomena. They may or may not play a part in control of energy metabolism. When blood sugar dips too low, orexin neurons seem to be activated.
When orexins are injected into animals, the blood pressure and heart rate increase. The animals experience lower levels of luteotropic hormone (important in the immune system) and growth hormone in the blood and higher levels of stress markers corticotropin and cortisol. Insulin levels also rise. (details)
British researchers have shown that orexin neurons can be activated by specific mixes of dietary amino acids and that this is a separate stimulation from the blood sugar signal.
This is all interesting, but working out the connections in their complexity has not been accomplished yet. Perhaps the diet pills of the future will affect the orexin circuit.
One hypothesis for the cause of some depression is insufficient serotonin and noradrenaline in parts of the brain. In recent times the thinking has focused more on neuropeptides. On theoretical grounds, orexins may be tied up with depression and offer a therapeutic path to treatment of depression, but there is insufficient understanding of how things work at a molecular level and no viable depression treatments based on the orexin circuit at this time.
Narcoleptics have abnormally low levels of orexin in their cerebrospinal fluid.
Here is a good study of deficiency in the brains of people with narcolepsy and primary hypersomnia, Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia.
Experiments with delivering orexins to narcolepsy patients through a nasal spray have produced promising results but more work is needed before therapies become available.
Orexin neurons and the orexin circuit do not appear to play apart in cocaine addiction.
Studies have shown that orexin levels do not change with age in the brains in people without narcolepsy so age-related sleep disorders do not appear to be a function of orexin levels.
But experiments on rats have suggested changes in the hypothalamus orexin neurons may cause age-related dysfunctions in arousal, learning, and memory. Elderly rats do not seem to respond to external administration of orexin as much as younger rats do,
Drugs To Influence the Orexin Circuit
Pharmacological interventions into the orexin circuits are tempting to the drug companies and to medical professionals interested in treating insomnia and sleep-wake disorders. The term “agonist” refers to compounds that in some way replicate natural bodily chemicals. The agonists attach to the “receptors” – in this case in brain cells – and mimic the orexin. “Antagonists” are the opposite and block receptors from connecting with the body’s hormone. Classifying bioactive materials as agonists and antagonists in relation to a target is a common way to think about drugs and to pursue their development.
For orexins, agonists would be drugs that increase alertness and wakefulness, and would be useful in treating hypersomnia and narcolepsy. They would replace or compete with modafinil, methylphenidate, and amphetamines. Antagonists would reduce the effect of orexins in the brain and induce sleepiness. They would be useful in treating insomnia and have the potential to help millions of people.
Further, this avenue of intervention in sleep physiology is a new frontier and is intellectually exciting to the researchers. And instead of affecting the GABA circuit as most prescription sleep aids do, they would go through another circuit, perhaps a more subtle way to induce sleep and avoid the interruptions in sleep architecture that current sleeping pills cause. It is estimated the brain contains 70,000 to 100,000 orexin neurons, mostly in the hypothalamus. By contrast there are 500 million GABA neurons spread throughout the brain so orexin drugs can potentially be more targeted. Experts worry that such drugs would have different, but still serious side effects as compared to existing drugs – including cataplexy and respiratory system effects. It remains to be seen what type and severity of side effects any new drugs have.
Pharmaceutical companies are spending millions in developing both orexin agonists and antagonists, and so far: nothing. No drug has reached the market or appears to be close to doing so. But research continues.
And what of performance-enhancing drugs? If orexins are part of the arousal circuit, maybe pharmaceuticals that increase orexin levels could make normal waking even more – wakeful? Could we see the use of such drugs to make healthy people better than well? Plenty of “smart drug” enthusiasts speak of intranasal orexin sprays to ward off sleepiness and while such sprays have been used experimentally on narcoleptics, they are not widely available to the public or approved by regulators for any condition.
Curiously, a study found that play increases the levels of orexin in the body, but that cardiovascular activity does not. What does this mean as a practical matter? It speaks of the goodness of play.