Today’s post is rather lengthy, as I’m quite enthralled with the information I’ve found. I will bold major points or sentences for those who wish to skim over and get the basic jist instead of reading the content in its entirety.

This week I ended up down an exciting and fascinating rabbit hole. It was prompted last Thursday by a conversation I was a part of with a medical student at work. He mentioned a study where it was found that cerebral spinal fluid (CSF) actively circulates through the brain during sleep to remove metabolic byproducts or “toxins” (I hesitate to use that term because of how it’s been tainted by cleanse diets). In particular, this study was looking at the protein found in abundance in the brains of Alzheimer’s patients. It builds up in the brain as the day goes on, and then it flushed out at night by CSF.

I then took to Google to try to find this particular study so I could learn more about it. However what I ended up finding instead was a research paper from the late 80s where the CSF of sleep deprived cats, and vasoactive intestinal polypeptide (VIP) were injected into cats who had been given parachlorophenylalanine (PCPA). The PCPA-induced insomnia was reversed by the CSF and VIP.

This is now where the rabbit hole begins. I found a research paper by Donald R. Staines from 2004 entitled “Is fibromyalgia an autoimmune disorder of endogenous vasoactive neuropeptides?” which discusses some of the function of vasoactive polypeptides and how autoantibodies to them could be responsible for the symptoms we see in fibromyalgia. Before I dive into medical jargon, let’s begin by explaining what vasoactive neuropeptides are.

Vasoactive Neuropeptides

Neuropeptides are short-chain polypeptides that act as neurotransmitters. To break that down: polypeptides are chains of amino acids, and neurotransmitters are endogenous (meaning they originate from within the body) chemicals that enable neurotransmission, which is the transmission of nerve impulses. So neuropeptides are short chains amino acids that enable transmission of nerve impulses like neurotransmitters do. However neurotransmission isn’t the only possible role for vasoactive neuropeptides. They also can act as hormones, immune modulators, and neurotrophes [Staines].

A few other neat facts about neuropeptides: they’re 1000 times more potent than neurotransmitters, cannot undergo reuptake, and take effect in a different location than where they’re produced (whereas neutotransmitters are released in direct apposition to their target cells). Examples of neuropeptides include oxytocin, vasopressin, TSH, and insulin.

Vasoactive means that they have an effect on the diameter of blood vessels, either expanding or contracting them. Because they’re vasoactive, they’re essential in maintaining vascular flow in organs [Staines].

Vasoactive neuropeptides regulate the inflammatory response in the body by being anti-inflammatory and protect the nervous system from toxic assault. Additionally they’re vital for thermoregulation, memory, and concentration. [Staines]

Vasoactive Intestinal Polypeptide

This particular vasoactive neuropeptide is produced throughout the intestinal tract and in both the peripheral and central nervous systems. It’s 50-100 times more potent than acetylcholine as a vasodilator. In the central nervous system, it helps to regulate cerebral blood flow, energy metabolism and enzymatic activity, is 20 times more potent than norepinephrine in stimulating the enzymatic breakdown of glycogen and glucose, and helps release corticotropin-releasing hormone, prolactin, oxytocin, and vasopressin. [Henning]

VIP has been shown to protect against glutamate-induced toxicity and plays an important role in regulating the circadian rhythm [Staines]. An imbalance between GABA and glutamate is currently the common thought for what’s wrong in FM patients, and lead to the use of GABA analogues like Lyrica for treatment. To compound, results from a 1997 study suggested that the activation of presynaptic VIP receptor enhances the GABAergic synaptic transmission in hippocampal neurons, and that VIP is likely to increase GABA release [Wang]. An abnormal circadian rhythm and digestive issues, including intolerance to sugars like glucose, is also common in FM patients.

But how is VIP released in the first place? It’s stimulated by high frequency (10-20 Hz) nerve stimulation and by cholinergic agonists (medications that mimic acetylcholine like Salagen and Evoxac), serotonin, dopaminergic agonists, prostaglandins (PGE, PGD), and nerve growth factor [Henning]. In a study from 2004, rats with Parkinsons were treated with 25 ng/kg of VIP at two day intervals for a period of 15 days. The results showed that VIP significantly increased levels of GABA and the number of nerve growth factor (NGF) immunoreactive mast cells, but did not alter dopamine metabolism. What I find particularly interesting about this is that modafinil, which is for narcoleptics and increases dopamine, is one of the drugs that has helped my symptoms significantly. As well as antidepressants that inhibit serotonin reuptake, and of course Lyrica which is a GABA analogue.

Autoimmune Implications

It’s an extremely common trend that people develop FM after some sort of physical trauma. When the body encounters some form of injury, there is a natural inflammatory response where pro-inflammatory cytokines are released to induce inflammatory symptoms. VIP regulates these cytokines, however if there was autoimmune dysfunction involved, it’s possible that both the vasoactive neuropeptides and their receptor sites are being impaired by autoantibodies, resulting in the inability to properly regulate the inflammatory response. If a large injury were to occur, the response would be large in scale, and because of impairment from autoantibodies, the body would not be able to restore homeostasis. Indeed, pro-inflammatory cytokines in the skin tissue of patients with FM have been observed and would support this hypothesis.

It’s also been observed that levels of anti-VIP antibodies (AVA) can increase with physical activity, most likely to protect from effects of excessive VIP in response to inflammation [Shoemaker]. If there already is an autoimmune dysfunction of AVA in patient with FM, this could be explanation for why exercise and physical exertion only worsen the symptoms of those with FM and other such conditions.

Conclusion

All of this information shows promise for finding out more appropriately what causes fibromyalgia symptoms. This is the only bit of research I’ve found thus far that directly touches all of my symptoms: sleep disturbance, digestive upset, memory, concentration, fatigue, overall feeling of inflammation, poor circulation, heart rate abnormalities, thermoregulation, and exercise intolerance. This has opened up a new avenue of research for me to delve into, and I will try to keep this blog updated with what I find.

Citations

Henning, Robert J and Sawmiller, Darrell R. “Vasoactive intestinal peptide: cardiovascular effects” Cardiovascular Research 49 (2001): 27-37. Elsevier.

Korkmaz OT, Tunçel N, Tunçel M, Oncü EM, Sahintürk V, Celik M. “Vasoactive intestinal peptide (VIP) treatment of Parkinsonian rats increases thalamic gamma-aminobutyric acid (GABA) levels and alters the release of nerve growth factor (NGF) by mast cells.” J Moi Neurosci 41 (2010): 278-287.

Shoemaker RC, Katz D, Ackerley M, Rapaport S, McMahon S, Berndtson K, Ryan JC. “Intranasal VIP safely restores volume to multiple grey matter nuclei in patients with CIRS” Internal Medicine Review Vol 3, Issue 4 (2017).

Staines, Donald R. “Is fibromyalgia an autoimmune disorder of endogenous vasoactive neuropeptides?” Medical Hypotheses 62 (2004): 665-669. Elsevier.

Wang HL, Li A, Wu T. “Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons” Brain Research 746 (1997): 294-300.