Orexin system disruption may be driving Long COVID symptoms and chronic health issues

Medical News: Orexin Dysfunction May Be the Missing Link Behind Long COVID Symptoms and Related Chronic Health Problems
 
Researchers from the Department of Cardiology, Angiology and Critical Care Medicine at Philipps University Marburg in Germany and the State of Hessen Post-COVID Coordination Center are shining a spotlight on a lesser-known but potentially critical factor in understanding the root causes of Long COVID or post-acute sequelae of COVID-19 (PASC) - the orexin system. In their newly published study, scientists detail how disturbances in the orexin network may be driving many of the mysterious and persistent symptoms seen in patients months or even years after recovering from an initial SARS-CoV-2 infection.


 
Orexins - also known as hypocretins - are neuropeptides that play an essential role in regulating wakefulness, energy metabolism, cardiovascular function, appetite, and the body’s autonomic nervous system (ANS). When this system is thrown off balance due to inflammation, neuronal damage, or autoimmune attacks, it can manifest in debilitating symptoms such as fatigue, dizziness, sleep disturbances, brain fog, heart irregularities, and more - all hallmark symptoms of Long COVID. This Medical News report will delve into the detailed mechanisms behind orexin dysfunction and how it could be the unifying explanation for a wide range of lingering COVID-related symptoms.
 
The Orexin System Explained
Discovered in 1998, orexins are peptides produced in a specific region of the hypothalamus and are known to influence numerous biological functions through their interaction with orexin receptors (OX1R and OX2R). These receptors are distributed throughout the brain and body, allowing orexins to influence everything from sleep-wake cycles and metabolism to emotional regulation and blood pressure.
 
The researchers noted that although most studies on orexin distribution were done in rodents, the orexin system is highly conserved across species, making it applicable to human health. Orexin-producing neurons project throughout the brain, influencing regions involved in attention, pain perception, reward, and autonomic control. Disruption to this vast network could easily produce multisystem symptoms.
 
Orexin Dysregulation and the Autonomic Nervous System
One of the most critical functions affected by orexin imbalance is the autonomic nervous system. Orexins are involved in regulating sympathetic nerve activity - especially through regions such as the rostral ventrolateral medulla (RVLM), which influences cardiovascular control. Animal studies show that injecting orexin peptides can lead to increased heart rate, blood pressure, and catecholamine levels. However, in models where orexins are absent, the opposite is observed - lower blood pressure and blunted stress responses.
 
This interaction explains why many Long COVID patients experience disorders like Postural Orthostatic Tachycardia Syndrome (PoTS), which causes lightheadedness, palpitations, and excessive heart rate upon standing. PoTS is frequently diagnosed in people with Long COVID and is believed to result from dysregulation in autonomic reflexes - somethin g that could stem from a malfunctioning orexin system.
 
Cardiovascular and Metabolic Implications of Orexin Imbalance
Beyond the nervous system, orexin peptides directly influence cardiovascular health. The study highlighted orexin’s role in modulating nitric oxide pathways, which can either dilate or constrict blood vessels depending on the context. This dual capability might help explain the erratic blood pressure swings seen in many Long COVID sufferers. Moreover, orexin appears to reset baroreflex thresholds - an essential process in maintaining circulatory stability.
 
Orexins also impact endothelial function. Orexin-A can suppress inflammation in blood vessels caused by oxidized LDL (a contributor to atherosclerosis) and boost the repair of damaged vasculature. Given that endothelial dysfunction is a known feature in both acute COVID-19 and ME/CFS (a condition often overlapping with Long COVID), a disturbed orexin system could be a key factor behind vascular symptoms.
 
Furthermore, orexin regulates metabolism by influencing glucose uptake, fat storage, insulin sensitivity, and even thermogenesis via brown adipose tissue. Studies showed orexin gene expression was linked to insulin resistance and dyslipidemia - both of which are increasingly reported among COVID-19 survivors. Interestingly, the anti-diabetic drug metformin has shown promise in preventing PASC, suggesting metabolic pathways play a critical role.
 
The Orexin Network and Neurocognitive Symptoms
One of the most debilitating aspects of Long COVID is its impact on the brain. Brain fog, memory loss, mood changes, and sleep disorders are all common. The study outlines how orexin neurons are deeply integrated into neural circuits that regulate cognition, mood, pain, and sensory processing. These neurons interact with numerous other neurotransmitters - dopamine, serotonin, GABA, acetylcholine, and even endocannabinoids - to maintain homeostasis.
 
The researchers found that orexin dysfunction could disrupt these interactions, leading to neurocognitive symptoms similar to those seen in conditions like narcolepsy or ME/CFS. In fact, orexin deficiency is already known to cause narcolepsy, a condition marked by daytime sleepiness, hallucinations, and disrupted sleep architecture - symptoms increasingly reported in Long COVID.
 
The team also noted that COVID-19 infections have been associated with new-onset narcolepsy in some cases, suggesting a potential autoimmune or inflammatory attack on orexin-producing neurons. Further supporting this idea, researchers found autoantibodies targeting the OX2R receptor in some COVID-19 patients, correlating with low consciousness levels.
 
Orexin’s Role in Neuroinflammation and Immune Modulation
Perhaps most intriguing is the potential role of orexins in modulating inflammation. COVID-19 and Long COVID are associated with chronic immune activation and neuroinflammation. Orexin-A has shown neuroprotective effects in mouse models, including reduction of pro-inflammatory cytokines like IL-6 and TNF-α. When administered intranasally, orexin-A reduced glial cell activation - suggesting a way to calm overactive microglia in the brain.
 
These anti-inflammatory effects extend beyond the brain. In models of colitis and joint inflammation, orexin-A outperformed even standard drugs like infliximab by reducing cytokine storms, oxidative stress, and tissue damage. The peptide also helped restore the intestinal barrier - a feature compromised in both COVID-19 and autoimmune diseases.
 
The researchers proposed that orexin signaling might represent a built-in mechanism to balance immune responses. When dysregulated, this protective system could fail, allowing runaway inflammation and autoimmunity to take hold - common themes in Long COVID.
 
Sleep Disturbances and the Orexin System
Sleep disorders are one of the most consistent complaints among Long COVID patients. Orexin neurons play a central role in wakefulness and sleep regulation. Disruption to this system leads to fragmented sleep, insomnia, and excessive daytime fatigue. Sleep deprivation itself causes cognitive and emotional changes, further compounding the neurological burden of Long COVID.
 
Interestingly, treatments that target orexin receptors - especially receptor antagonists or agonists - have shown promise in treating sleep disorders. Their role in Long COVID is still being explored, but they may represent a future avenue for managing persistent symptoms.
 
Conclusion
The study underscores the possibility that orexin dysfunction may be a unifying mechanism behind many of the debilitating symptoms associated with post-COVID syndrome. From regulating cardiovascular stability and metabolic function to maintaining cognitive clarity and immune balance, the orexin system touches nearly every aspect of human physiology. When disrupted - whether by direct viral injury, immune response, or autoantibodies - this system could spiral into widespread dysregulation seen in Long COVID patients.
 
Although more research is needed, the insights provided by this team of German scientists offer promising new avenues for therapy. Treatments that stabilize or enhance orexin function - especially intranasal orexin-A or receptor-targeting drugs - could potentially alleviate many symptoms that currently have no cure. Additionally, orexin modulation may help correct the underlying inflammatory and metabolic abnormalities that drive chronic illness in COVID survivors.
 
For now, the orexin system deserves much more attention in ongoing Long COVID research and treatment development. Unlocking its secrets may lead to the breakthrough millions of sufferers around the world have been waiting for.
 
The study findings were published in the peer reviewed journal: Biomedicines
https://www.mdpi.com/2227-9059/13/3/545
 
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