If you experience chronic, extreme fatigue, you need to know about orexins. Orexins are like norepi or dopamine -on steroids. They have powerful “anti-fatigue” effects in addition to controlling a wide range of physiological activities.

  • 1.About Orexins and Symptoms of Orexin Deficiency

  • 2.Orexins In The Brain

  • 3.Orexin In The Gut/Role In Metabolism

  • 4.Orexins and Autonomic Nervous System (ANS)

  • 5.Orexin And Pain

  • 6.Orexin And Hormones

  • 7.Orexins And Motor Activity

  • 8.Orexin System in MS, Parkinson’s and Other Brain Conditions

  • 9.Could Orexin Deficiency Be The Hidden Cause of MS ?

How To Treat Orexin Deficiency Naturally- In This Article

1.About Orexins and Symptoms of Orexin Deficiency

I wrote about norepinephrine, an important neurotransmitter/ hormone involved in “fight or flight” reaction that keeps you awake and alert, and how fatigue is a key symptom of norepi deficiency. Dopamine, serotonin and acetylcholine deficiencies can also lead to fatigue.Technical: Orexin neurons have a stimulating (excitatory) effect on every wakefulness promoting neuronal group tested by researchers so far, according to a 2015 study [1].  

Here is a good example to remember the role of orexins in wakefulness: narcolepsy, a condition characterized by excessive daytime sleepiness, episodes of falling asleep during the daytime and sudden loss of muscle tone is caused by loss of orexins (90% of orexin neurons are lost in narcolepsy) [2]

Do you have some of the following symptoms ?

  • Extreme fatigue with day time sleepiness

  • Sleeping problems, fragmented sleep

  • Lack of motivation

  • Anxiety/panic attacks

  • Depression

  • Addictions

  • Low blood pressure

  • Slow digestion/constipation

  • Muscle weakness, difficulty walking

  • Headaches/migraines

  • Tingling and numbness

  • Excessive sweating

  • Lack of sex drive

These symptoms can be due to orexin deficiency. 
Orexins, also known as hypocretins are neurotransmitters/hormones. Orexins had been discovered in the late 1990s, and we have now hundreds of research papers about them. Yet, very few people know about how important they truly are. There are two types: orexin -A and orexin B [3].  Technical : The orexin system consists of two G-protein coupled receptors (the orexin-1 (Ox1) and the orexin-2 (Ox2) receptor) and two neuropeptides, orexin-A and orexin-B which are both produced from prepro-orexin in the lateral hypothalamus [4].There are only 30,000 to 70,000 orexin producing neurons [5].

Although the orexin producing neurons are located in a small area of the brain (in a few nuclei of hypothalamus), their nerve fibers spread out through the entire brain, being involved in many important functions, including wakefulness and feeding.

2.Orexins In The Brain: 

  • promote wakefulness/arousal  during the day and good sleep at night

  • role in memory and learning

  • involved in motivation/reward system

  • stimulate other neurotransmitters (serotonin, norepi, dopa, acetylcholine)

  • regulate emotions and behaviour  – make you feel happy

  •  anti-anxiety /antidepression qualities

  • role in thermoregulation

Orexin neurons innervate and activate brain areas that promote wakefulness. Orexins activate the orexin producing neurons, but also dopamine, norepinephrine, serotonin, histamine and acetylcholine producing neurons in the hypothalamus/brainstem regions to maintain wakefulness. Orexin deficiency causes daytime sleepiness, fatigue, fragmented sleep at night and other sleep disturbances [6].It looks that orexin producing neurons also contain glutamate and orexins regulate glutamate release [7]. They also seem to play a role in memory and learning on their own (as well as by stimulating acetylcholine). Along with dopamine, they are involved in motivation/reward system and addictions thus orexin receptors are now a target for anti-craving medications.  Orexins stimulate amygdala, the part of the brain involved in emotions and behavior [9], [10],[11],[12] and orexin deficiency correlates with anxiety and panic attacks. Orexins have antidepressant qualities. Their antidepressant effects likely derive from orexin’s ability to promote formation of new cells in the hippocampus.  Low levels of orexins (and smaller hippocampus) had been documented in suicidal individuals with depression [13],[14],[15]. Orexins are involved in experiencing happiness [16].

Other neurotransmitters and hormones involved in happiness are: dopamine, serotonin, norepinephrine, endorphins, melatonin and oxytocin. Would you like to know which parts of the brain are involved in happiness ? As you may guess, hippocampus is one, along with prefrontal cortex, amygdale, anterior cingulated cortex, and insular cortex [17].

Orexins and thermoregulation: orexins are important in maintaining normal body temperature and how the body adapts to changes in environment. When you are exposed to heat, the body will try to cool down through various mechanisms (ie sweating). Research shows that decreasing basal body temperature (cooling-off) in response to hot environment is associated with a reduction in orexins, as well as PGE2 and COX-2 (all three molecules are key thermoregulatory molecules) [18].This means that someone with orexin deficiency may experience problems adapting to heat, and when he does, the shortage of this neurotransmitter is further aggravated, leading to typical symptoms of orexin deficiency listed above-including excessive sweating. 

3.Orexins In The Gut/Role In Metabolism

  • support gut health and gut brain axis

  • involved in sugar metabolism

  • regulate feeding and water intake

Orexin neurons are also found in the gut, in the enteric nervous system (ENS). Orexins support the gut-brain axis, by conveying sensory information from the gut to the brain. They help maintain healthy sugar metabolism, and the orexin system is found in pancreas as well, modulating the secretion of insulin (orexin -A particularly promotes insulin release) [19]. Orexins regulate the feeding process (they increase food intake) as well as water intake. Interestingly, they also speed the metabolism. Orexins stimulate the secretion of gastric acid and gut motility. They stimulate the brown fat (the “ good” fat, involved in weight loss and maintain body temperature) [20],[21]. Orexin deficiency is also associated with increased food intake and obesity (increased “white “fat, the bad one we all know). Orexin deficiency also slows digestion causing constipation and low stomach acidity (which can lead to food sensitivities/intolerances and many other problems).

4.Orexins and Autonomic Nervous System (ANS)
ANS has three branches: the sympathetic nervous system (involved in fight or flight reactions), the parasympathetic nervous system (rest and digest) and the enteric nervous system (in the gut). Orexins stimulate the sympathetic nervous system, having an impact on cardiovascular system, body temperature and metabolism Orexin deficiency is associated with low blood pressure and low heart rate, as well as disruption in the body temperature [22],[23] and excessive sweating.

5.Orexin And Pain

  • orexins work as painkillers 

Orexins send signals to the cranial and spinal nerves, acting as painkillers Orexin deficiencies correlate with migraines/ headaches and neuropathic pain (tingling and numbness) [24],[25]. How it works: pain and stress activate orexins. When the orexin system is activated, it will delay pain transmission. In a study conducted in animal models, orexin A (intravenous) showed the same efficacy with morphine [26],[27].

6.Orexins And Hormones

Orexins increase the blood pressure and heart rate, promote the release of certain hormones (insulin, LH, GH, PRL, leptin, TRH). They have a strong impact on hypothalamic-pituitary-thyroid axis [29]. Estrogens influence the effect of orexins on LH release and orexin receptors stimulate the production of estrogen and testosterone.

7.Orexins And Motor Activity

Orexins  are very important for movement. They seem to promote the voluntary movements, as they activate the neurons in the motor cortex. Orexin deficiency leads to motor deficits and muscle weakness. Technical: high density of orexin-immunoreactive fibers in the motor control system include motor cortex and basal ganglia, but also found in brain stem and cerebellum [28].

8.Orexin System in MS, Parkinson’s and Other Brain Conditions

  •  orexins play a key role in preventing and fighting neuroinflammation and neurodegeneration [30]

Technical: acting as an immunomodulatory regulator of microglia, decreasing pro-inflammatory cytokines and increasing anti-inflammatory factors to promote a favorable neuronal microenvironment [31],[32].Orexin A seems to be specifically able to prevent death of neurons in hippocampus[33].Orexin deficiencies are linked with motor and sensory deficits in animal model of Parkinson’s disease [34], Huntington’s disease, Guillain-Barre syndrome, neuromyelitis optica [35] and Alzheimer’s [36]. All these conditions are associated with loss of orexin producing neurons and decreased sensitivity of orexin receptors. Scientists found that people with Parkinson’s disease (late stage) have a 38% to 45% less of the orexins-producing neurons [37]. Research now suggest that orexin could be used as a biomarker of neurodegeneration [38].

9.Could Orexin Deficiency Be The Hidden Cause of MS ?

I wrote  before about Dr. Fromell’s theory: norepinephrine deficiency as a cause of MS [39]. Dr. Brunes further developed this theory and is treating MS by correcting neurotransmitter deficiencies. Norepinephrine deficiency is highly suspected when fatigue is the chief complaint associated with MS. More details about Dr.Brunes treatments here. The concept is brilliant, but was created a few decades ago, in the 1980s.

I think is about time to update this theory with more recent research- and include the critical role of orexin deficiency as a cause of MS. While norepinephrine is important, orexin is even more powerful -whether you want to manage fatigue or other symptoms of MS.

Fatigue affects up 90 % of people with MS, and is often more debilitating than walking problems or other symptoms. Based on current research, there are three main reasons why fatigue develops. As you may guess, orexin deficiency is one. The second reason is an overall activation of the HPA axis. The hypothalamic pituitary adrenal (HPA) axis is the central stress response system, linking the central nervous system with hormones. The last reason involved in the development of fatigue: abnormal cortisol levels. These three reasons of fatigue are all connected, by the way.

Let’s get back to orexins. In relation to MS, research focused on orexin deficiency and its association with fatigue and disturbed sleep. The orexin system is very sensitive to inflammation. Therefore, the brain inflammation (neuroinflammation) from MS reduces the activity of orexin producing neurons, and therefore fatigue. Some case reports evaluating people with MS show that brain lesions involving hypothalamus (where orexin is produced) and low levels of orexin in the cerebrospinal fluid (CSF) correlate with increased sleepiness and fatigue. Another study showed that low orexin levels correlate with the severity of fatigue, and this correlation was even stronger in the MS subgroup that suffered from fatigue. Another research paper noticed an association between narcolepsy and MS, explained by the fact that both have similar genetic component : HLA-DR2 positivity (so an autoimmune target on the same brain structures has been thought to be a common cause for both MS and narcolepsy). MS also shares similar symptoms with narcolepsy- for example extreme fatigue, insomnia, REM sleep abnormalities and other sleep disturbances. Other studies found conflicting results, or did not find any link between orexins and MS ie changes orexin levels in people with MS versus those without MS. We definitely need more studies on this topic.

What I would like to point out is that correcting orexin deficiency would not only improve fatigue and sleep problems, but also pains (headaches, numbness, tingling), dysfunctions of the autonomic nervous system (low blood pressure, troubles regulating body temperature), decrease brain inflammation and degeneration, digestive symptoms (ie constipation) and improve walking and muscle tone. As you can see above, orexin deficiency play a key role in all these issues.

A few more thoughts: Orexin deficiency may not be seen in everyone with MS, just the same way not everyone will have dopamine or serotonin deficiencies. However, orexin deficiency should be highly suspected in all cases where fatigue is the chief complaint.

At the end of the day, this is important to know: 1.MS is associated with neurotransmitter imbalances (orexins and/or other neurotransmitters) and 2. There is a complex mechanism that creates orexin deficiency- there is hypothalamic dysfunction in MS, and hypothalamus has many other roles in brain health and 3. Cutting down the neuroinflammation, improving sugar metabolism will improve the balance between neurotransmitters and the brain function, while decreasing the neurodegeneration and the progression of the disease.

Using orexin system as a therapeutic target makes a lot of sense- for example using orexin receptor antagonists at night and orexin agonists during the day. Current drugs used for managing fatigue for MS — ie modafinil, methylphenidate, amantadine do influence orexin system either directly or indirectly [40],[41],[42].

 

How To Treat Orexin Deficiency Naturally- In This Article