Chicken vs Egg vs House-on-Fire vs Other Analogies

A short post on the tangled knot of Fibromyalgia/MECFS etiology and sustained allostasis.

I'd like to start with a situation many of us will have encountered. A friend, family member, or doctor will say something like:

"You're complaining about a lot of symptoms. You can't possibly have so many things going wrong!" 

This is akin to a firefighter showing up to a burning building and saying:

"More than one or two rooms are on fire? How could the whole house be on fire?!"

A house on fire serves as a decent analogy. The fire may have started in one room, but if it was not put out promptly, it will have spread to the whole house. Now it doesn't matter much where it started, every room must be doused. The same is true with these nebulous neuroimmune conditions.

Unusual infections, unusually high numbers of infections, and unusual presentation/persistence of 'common' infections are frequent findings (or at least theories) in MECFS and fibromyalgia. Do they clear up but leave the immune system exhausted, or does a preexisting immune issue allow them entry? This is a Chicken-and-Egg question that doesn't really provide much solace to the suffering.

Many things can subtly weaken the immune system: genetic predisposition, nutritional deficiencies, toxin exposure, dysbiosis, and ANS dysregulation. This last one can be due to PTSD, chronic stress, or an extremely 'Type-A" personality. All these things can alter the functioning of the HPA-axis, subsequently knocking the nervous system and endocrine system out of line. This domino effect then hits the immune system. Unfortunately, these dominos are arranged on something like MC Escher's infinite stairs (Penrose Stairs). Problems with the immune system can interfere with the nervous system, endocrine system, detoxification, etc. As soon as one domino, one body system, tries to get on its feet it gets knocked back down by the the collapse of another.

A final analogy: imagine your body systems as a collection of friends marching forward together as you journey through life. If one or two of these friends get sick or injured they can lean on the others for support. But if most of them are sick, or hopping around on one leg, then when they turn to each other for support they're more likely to just knock each other over. In systems engineering, this is termed Cascading Failure:
https://en.wikipedia.org/wiki/Cascading_failure

The good news is that if you work on several body systems at once, some of them can become robust enough to start to pull the others back up too.


Thanks for reading. For science-based discussions of how different body systems interact, check out some of my older posts. Deeper discussion is forthcoming (there's a lot of medical literature to dig through!)

How nutritional deficiencies can make viruses worse:
http://lavenderdojo.blogspot.com/2016/04/mutant-viruses.html

How molecules of the immune system can make pain worse:
http://lavenderdojo.blogspot.com/2016/03/pain-and-inflammation-nociception-and.html

How molecules of the immune system can cause low energy and brain fog:
http://lavenderdojo.blogspot.com/2016/05/thyroid-immune-interactions-rt3-and-tgf.html



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Addenda
Some studies that look promising:

This can't be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response.

http://www.ncbi.nlm.nih.gov/pubmed/26409212

Caudle M. This can’t be stressed enough: The contribution of select environmental toxicants to disruption of the stress circuitry and response. Physiol Behav. 2015

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181830/?report=reader
Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues in Clinical Neuroscience. 2006;8(4):383-395.

(for this last study, if you use the search function in the upper right-hand corner, you can find little nuggets by searching "immune")

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress

May 12th Awareness Day

Today is May 12th, Invisible Illness Awareness Day / M.E. Awareness Day / Fibromyalgia Awareness Day. I would like to share Hanlon's Razor:

Never attribute to malice that which can be adequately explained by stupidity

I'm not saying there has never been foul play in the history of how these conditions are viewed/treated, but I do think ignorance and misinformation (and biomedical limitations for testing biomarkers) are the primary drivers. That's why awareness days are important. 

For fibromyalgia, I made a short video that attempts to shed a little light on the nature of invisible pain. It didn't quite go as I'd liked, but I guess I can always burn myself on camera again, in a more grisly fashion, hah, heh, ergh. 

Oh, any ideas for things traditionally considered painful that don't do lasting damage? Leave suggestions in the comments please!

https://www.youtube.com/watch?v=iX1Vgl0GCKQ

Pairs well with my post on nociceptors and cytokines:

http://lavenderdojo.blogspot.com/2016/03/pain-and-inflammation-nociception-and.html

I've heard it put forth that Flea of the Red Hot Chili Peppers had MECFS for a few years. So, via some kind of logic (or lack thereof) here's a RHCP cover:

https://www.youtube.com/watch?v=AtpCO3S18Dc

Over the years of feeling ill, songwriting was an outlet that helped keep me sane. I particularly like finding slant-rhymes for tricky words like 'orange' and 'chrysanthemums'. Digital art is also fun:

Combine all that with digging through hundreds of medical studies, and the existential crisis that occurs after years of being sick and maligned, and yarr: a song about science and religion teaming up to fight disease

https://www.youtube.com/watch?v=euXi86vrGHM

Best of luck on your road to recovery. Or, if you're not ill, please be understanding towards those who are.

Sean @ LavenderDojo

Thyroid-immune interactions; rT3 and TGF-beta1

Let's cut right to the core study:

Transforming Growth Factor-β Promotes Inactivation of Extracellular Thyroid Hormones via Transcriptional Stimulation of Type 3 Iodothyronine Deiodinase

Stephen A. Huang, Michelle A. Mulcahey, Alessandra Crescenzi, Mirra Chung, Brian W. Kim, Carmen Barnes, Wichert Kuijt, Helen Turano, John Harney, and P. Reed Larsen

Molecular Endocrinology 2005 19:12, 3126-3136

That title should link to the full study. Here's the abstract on PubMed:
http://www.ncbi.nlm.nih.gov/pubmed/16037131

Why is this important from a general biomedical standpoint? It shows that in the periphery (i.e. outside the thyroid itself) molecules of the immune system can affect the signal cascade of thyroid hormones. More specifically, a cytokine involved in inflammation can drive symptoms of hypothyroidism (e.g. low energy, depressed mood, cold extremities). This makes intuitive sense, the body is shunting energy away from quotidian activities in order to combat the source of inflammation. Under normal circumstances this works just fine: you get a severe tissue injury or a case of the flu, rest for a few days, then get on with your life. Unfortunately the modern world abounds with things that can drive chronic inflammation, and thus chronic hypothyroidism-esque symptoms. Though thyroid hormones may be involved, abnormalities won't necessarily be detected by standard thyroid work-ups.

As mentioned in the abstract of the above study, Type 3 Deiodinase (Dio3), is an enzyme that converts T4 into the inactive Reverse T3 (rT3). In normal healthy functioning the other deiodinases convert T4 into T3. T4 is produced by the thyroid, circulates in the blood and is converted into T3 by the liver, or by other cells of the body when they need T3. Compared to T4, T3 is the mover-and-shaker; it triggers metabolic changes, acts as a transcription factor for genes, and is a real go-getter. For day-to-day functioning you need your thyroid to produce adequate T4, and you need the other cells of your body to efficiently convert it into active T3, not rT3.

Transforming Growth Factor Beta1 (TGF-β1) is a pleiotropic cytokine. "Pleiotropic cytokine" is a complicated phrase, and yet it doesn't even come close to capturing how complicated TGF-β1 is. Cytokines are signaling molecules of the immune system, but TGF-β1 can be produced by other cell types as well (such as those involved in laying down the extracellular matrix that connects cells). "Pleiotropic" means it has many functions, often functions that would seem to be unrelated. TGF-β1 shows up in studies of wound healing, in studies of autoimmune disease, in studies of cancer, in studies of kidney disease, in studies of schizophrenia... the list goes on.

I first became interested in TGF-β1 because my rheumatologist tested my levels as part of extensive bloodwork. After 8 years of feeling incredibly sick it was the first test that came back unequivocally out of range. My rheumatologist says he sees highly elevated TGF-β1 in almost all of his fibromyalgia and MECFS patients. 

In recent months I have been sifting through papers on TGF-β1, with a particular interest in how it pertains to fibromyalgia and MECFS. A thorough blog post is forthcoming (hopefully within a week of this post, health allowing).

Prior to finding this wonderful rheumatologist I had spent years oscillating between visiting MDs (who usually treated me like a hypochondriac) and alternative practitioners (who didn't help much either). Constant fatigue made me suspect I had thyroid issues. A series of doctors refused to dig much deeper than measuring TSH, which was always in normal lab ranges. I became a bit pushy with a Physician's Assistant and managed to procure a Free T3, but it was also within normal range, albeit at the low end. Fortunately I stumbled upon WellnessFX and their thyroid panel:

http://www.wellnessfx.com/thyroid

Some things were out of range, but when I presented my doctors with my privately-ordered results they were dismissive. Oh. Kay. Then.

Further propitious interweb ambling led me to Stop The Thyroid Madness and its handy Reverse T3 calculator:

http://www.stopthethyroidmadness.com/rt3-ratio/

My ratios were completely out of whack. No wonder I had extreme fatigue. I felt validated by finally pinning down the fabled Objective Quantifiable Biomarker.

Ah, but the Unicorn had not been trapped by a qualified medical professional! That second step of validation didn't come until over a year later. I was fortunate enough to find the aforementioned rheumatologist. He takes a holistic approach to biomarkers, and does not treat patients with iatrical condescension. It was he who corralled a real Chimera, a beast I had not even heard of before:

Transforming Growth Factor Beta1

Additionally, he was not fazed when he saw my WellnessFX thyroid panel. Right away he looked at my rT3/T3 ratio. In his clinical experience, this is another element that is commonly misaligned in fibromyalgia patients. After a few months under his care my energy and cognitive function began to improve and I redoubled, 'requadrupled', 'reoctupled', and eventually 'rehexadecimalled' my meanderings through PubMed. I became curious about a possible link between my primary biomarkers. Sure enough, a simple Google search for "transforming growth factor beta deiodinase" returned the above study as the top result. You can try this yourself, and I strongly advocate this approach in general; if you juxtapose two arcane terms in a Google query you'll always get interesting results.

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Post Script:

In the process of preparing this blog post I found several other relevant studies. Due to time and energy constraints, I'll have to defer them to a later post. As a teaser, I'll say that they show further interactions between (other) cytokines and (other) deiodinases. If you're curious/impatient, I encourage you to try the Googling method mentioned in the previous paragraph. You might find things I've missed! :)

Also, it appears that neurons have receptors for T3, but not the necessary deiodinases to convert T4 to T3. This vital task is handled by neighboring glia. I find this particularly interesting because microglia (the immune cells of the brain) have been implicated in fibromyalgia and MECFS. Perhaps if microglia are busy fighting off invaders (be they active pathogens, or inert inflammatory molecules) they are impaired when it comes to producing T3 for neurons. This could be a cause of brain fog.

...Okay, I should at least track down and post that last study:

Thyroid Hormone and the Neuroglia: Both Source and Target

http://www.hindawi.com/journals/jtr/2011/215718/

Petra Mohácsik, Anikó Zeöld, Antonio C. Bianco, and Balázs Gereben, “Thyroid Hormone and the Neuroglia: Both Source and Target,” Journal of Thyroid Research, vol. 2011, Article ID 215718, 16 pages, 2011. doi:10.4061/2011/215718

Abstract:

Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.

Thanks for reading, and best of luck on your road to recovery!

Sean of LavenderDojo

Consolidating Online Presence

(not particularly important post)

A little bit of housekeeping:
I'm preparing to post more content, higher quality content, in more mediums and through more channels. Hopefully my peregrinations on PubMed (and other knowledge I've garnered over the last decade of illness) will add value to the spoonie community. I'd like to put myself out there more, and make at least a modest positive impact.

Lavender Dojo
/
LavenderDojo

I'll endeavor to stick to this name. The intent is that it is unique enough to be a top hit on Google if you search for those words, but mundane enough to not need spelling out. For this blog, I was originally using the name Lavendogh. Lavendogh was a word I made up so that this blog was the only result for the query "lavendogh". Unfortunately, the spelling was not intuitive if I mentioned the blog name in conversation. The hope is that "lavender" and "dojo" are both common enough to not require explanation, but a weird enough juxtaposition to be memorable.

Over the years, I've also had very sporadic activity on Twitter and SoundCloud under the pseudonym Feeble Asclepius / @FeebleAsclepius. I intend to change those accounts to LavenderDojo also, but in case there are any hitches this blog post can act as a signpost.

Youtube account has gone from "phrygianechinoderm" to "lavendogh" and will presently be "LavenderDojo".

Uf! Online identity and digital footprints are interesting topics, but I digress. A series of important Fibromyalgia and MECFS posts are in the pipeline.

Mutant Viruses

As most people in the M.E. community know, there have been many red herrings and inconsistencies in the search for a specific viral trigger. Perhaps any one of several viruses can be a trigger in susceptible individuals - e.g. those of us with certain genetic polymorphisms, nutrient deficiencies, toxin exposure, chronic stress, PTSD, etc. It's also possible that some viruses may not always take their canonical form. Consequently standard antibody tests may not return conclusive results.

While parsing a paper on micronutrients, I came across an interesting passage:

A general overview of the roles of trace elements and immunity is incomplete without mention of the exciting discoveries by Beck and Levander. These investigators have shown that changes in the intracellular environment that are induced by alterations in micronutrient status can directly influence viral virulence and in addition can cause immune system dysfunction. The sentinel discovery is that selenium deficiency promotes the mutation of an avirulent strain of Coxsackie virus in the heart to a strain that causes myocarditis when the virus is passed from the selenium-deficient to a nutritionally adequate host (10). Because this modification of the viral genome also is observed in mice that are either deficient in vitamin E, overloaded with iron or lacking the glutathione peroxidase gene, it appears that the more oxidative intracellular environment that results from deficient or excess levels of some of the micronutrients promotes the genomic alteration that enhances virulence. The recent discovery that selenium deficiency also increases lung pathology in mice that are infected with influenza virus demonstrates that this effect is not limited to Coxsackie virus (11)

The paper that they refer to, by Beck and Levander, is an easy read (as medical papers go) and contains some brilliant detective work and beautifully orchestrated experiments. Check it out:

Selenium Deficiency and Viral Infection

http://jn.nutrition.org/content/133/5/1463S.full

In short, it was observed that Keshan disease was prevalent in areas of China with selenium-poor soil, and outbreaks followed a seasonal pattern, suggesting the involvement of a pathogen. An experiment with Selenium-deficient mice, and mice lacking the gene for glutathione peroxidase (a key enzyme in the antioxidant system) dovetailed with these findings. Most spectacularly, when healthy mice were injected with viral particles from Selenium-deficient mice, they developed the same pathology. The virus itself had changed!

The paper then explores some similar phenomena: mutations of the influenza virus in the presence of reactive oxygen species (ROS), and an outbreak of neuropathy in Cuba linked to nutrient deficiency, ROS, and viral mutation.

I did some preliminary searches of the literature for Epstein-Barr virus (EBV) mutations. EBV crops up frequently in theories of the etiology of M.E. Retrospectively, I've become suspicious that it had a roll in my development of fibromyalgia. I never had standard symptoms of Mononucleosis/Glandular Fever, but when my fibro symptoms first kicked off I had a nasty case of pinkeye. It was stubborn; after 2 years, a dozen ophthalmology/optometry visits, and numerous antibiotic drops, all it did was switch eyes. To this day, I still have a drooping eyelid, inflamed lid margins, light sensitivity, and a patchy tearfilm, but the worst of the pinkeye was cleared up by a few drops of colloidal silver. Those antibiotics hadn't worked because I did not have a bacterial infection. I had a viral one, perhaps EBV.

Anyway, to the literature search! This is just the tip of the iceburg, I'm sure. I wish I had more time and energy, but even a healthy person cannot sift through the 2.5 million studies on PubMed.

Well, well:

A comprehensive library of mutations of Epstein Barr virus.
http://www.ncbi.nlm.nih.gov/pubmed/17698655

An Epstein-Barr Virus (EBV) mutant with enhanced BZLF1 expression causes lymphomas with abortive lytic EBV infection in a humanized mouse model.
http://www.ncbi.nlm.nih.gov/pubmed/22623780

Reactive oxygen species mediate Epstein-Barr virus reactivation by N-methyl-N'-nitro-N-nitrosoguanidine.
http://www.ncbi.nlm.nih.gov/pubmed/24376853



When it comes to EBV, there's a lot to study. In future posts I'd like to discuss its effect on the Vitamin D receptor (VDR) and on cytokine expression.

There also, surely, is literature on mutations among other viruses of note. Go forth and trawl PubMed!


Other Sources:

Trace Elements and Host Defense: Recent Advances and Continuing Challenges

http://jn.nutrition.org/content/133/5/1443S.full.pdf

Selenium Deficiency and Viral Infection

http://jn.nutrition.org/content/133/5/1463S.full

Magnesium vs Drugs

Hours of browsing PubMed is making me delirious, but not yet delirious enough to patronize this film. Moving ahead to a better image:

Where to start? This table relates to yesterday's post about pain, inflammation, nociception, and cytokines. Blue entries indicate biochemical mechanisms that are, when it comes to analgesia, unequivocally beneficial. Red entries are more or less detrimental. The KOR column is green because the jury is out.

KOR stands for Kappa Opioid Receptor. This is one of the subtypes of opioid receptor in the body. It appears to be involved in reductions in pain, and yet is also associated with non-pain dysphoria. The body is complicated and fickle, eh?

MOR is the more familiar Mu Opioid Receptor. This is what opiates, and the opioid drugs inspired by them, bind to. Heroin, morphine, hydrocodone, oxycodone, etc are not created equal, but they all share a strong binding affinity for MOR. They also, frustratingly, lead to its down-regulation; over time they become less effective in reducing pain. In recent years, research has shown that they also bind to TLR4. This is bad because it triggers the release of proinflammatory cytokines, ultimately leading to increased pain and other unpleasant symptoms.

TLR4 is Toll-Like Receptor #4. This is part of the innate immune response. It cannonically  recognizes LPS, a substance on the cell walls of Gram-negative bacteria, a common class of pathogens. Contemporary research also suggests that it responds to various other ligands, such as DAMPs (Damage Associated Molecular Patterns). In short, TLR4 activation signals trouble to the body.

Amitriptyline is a tricyclic antidepressant. I added it to the table because I was pleasantly surprised to read that it is a potent antagonist of TLR4. This fact makes me more favorably inclined towards its somewhat common use in treating fibromyalgia and MECFS.

NMDA receptors are as complex as they are ubiquitous. For the purposes of this post, it suffices to note that they are a key point in the nociception-becomes-pain signal cascade.

Gabapentinoids (Gabapentin and Pregabalin) will be familiar to most fibromyalgia folks. Their primary mechanism of action is to lessen the flow of excitatory Ca2+ along the ion channels of axons. Magnesium ions, Mg2+, also attenuate this signal.

Magnesium is the hero of this story. Information about it abounds (just ask your friend Google). It is commonly deficient in the Western diet. It also has benefits far exceeding those listed in the above table (ask your friend Google). Hopefully, by juxtaposing it with drugs, this post adds some new elucidation. Caveat: the table says nothing of potency - magnesium has a broader spectrum of action than anything else in the table, but it was not pharmacologically designed with a particular aim. It's a Swiss army knife; if you need powerful scissors or a big screwdriver you'll have to look elsewhere. Consequently, if you start supplementing magnesium (as you probably should) don't immediately ditch your meds. I am not a doctor; if you sue me you won't get much money :)

Alcohol is in there for kicks. He's a fun guy, but don't spend too much time with him cuz things will get complicated quickly. In addition to the info in the table, alcohol increases the excretion of magnesium.

LDN - Low Dose Naltrexone! Low Dose Naltrexone deserves a lengthy post all on its own. Fortunately plenty of smart people have already written such posts (ask your friend Google). In short, it's an opiate turned inside-out and upside-down.

Anything I've missed: This post will be updated and refined as needed. At the moment I have a readership of 0 and a brainfog+fatigue of 7. Please leave a friendly comment if you need anything.

Sources: The sources are nonexhaustive, but exhausting; another task I'll defer until I'm recharged. If you're feeling adventurous you can always search PubMed (or your friend Google) for the juxtaposition of two terms (e.g. "amitriptyline NMDA")

Until next time, in the words of SuperBat: 

"So long, and thanks for all the fish"

Pain and Inflammation; Nociception and Cytokines

I'd like to start by marveling at a recent dramatic change in my fibromyalgia pain. After nearly nine years of intense burning pain through approximately 1/6 of my body I've now had 3 weeks of relief. On the left side of my body, my neck, shoulder girdle, pectoral, upper back, and the back of my head ached immensely. EVERY. WAKING. MOMENT. Currently that area feels normal, or occasionally tense - but no longer definitively painful. This is in large part due to decreasing systemic inflammation.

It shouldn't be a surprise that inflammation can cause pain. Everyone, not just fibromyalgia sufferers, has experienced the aching pains that accompany a flu. We've all noticed the localized pain that coincides with redness and swelling at the site of an injury. During inflammation the cytokines released by immune cells can stimulate nociceptors in the body.

Cytokines are signaling molecules released by immune cells in order to coordinate a response. Think of them as messages relayed by soldiers on a battlefield. Cytokines can also be released by other cells in the body in response to damage or threat. In this case they are similar to SOS messages from civilians.

Nociceptors are nerve cells that receive mechanical/electrical/chemical input and relay that input to the brain where it is transformed into the subjective experience of pain. They are analogous to the rods and cones in the eye that respond to photons and send a signal to the visual cortex, thereby giving rise to vision. You may have noticed that if you close your eyes and press firmly on your eyeballs you see some colors; the photoreceptors (rods and cones) are responding to a stimulus that they are not evolved to respond to, but they are responding nonetheless. Tinnitus is a similar phenomenon - noise generated in the absence of normal signal. A more mechanical analogy: sometimes electronic devices that are not radios will pick up signals from a radio station.

Enter the following quote from a biomedical study:

Today our understanding of this relationship is more detailed. When an antigen enters the body, local activation of immune cells leads to release of proinflammatory mediators, which are able to excite or lower thresholds of afferent nociceptive and afferent vagal nerve fibers [3]. If the neuronal signal strength is strong enough or if spillover of local inflammatory mediators into the circulation is robust enough, it signals to the brain, resulting in activation of the two major stress axes, the HPA axis and the SNS [3,4]. Cytokines like interleukin (IL)-1β [3,5] or tumor necrosis factor (TNF) [6] produced by locally activated innate immune cells are pivotal in this communication from immune system to central nervous system.

Afferent means a nerve fiber traveling from the body to the brain/central nervous system. *1

Thresholds. Neurons, including nociceptors, fire in an all-or-nothing fashion. They receive stimulation from neighboring neurons, or, in the case of nociceptors, from the adjacent environment. At any given moment, if the combined stimulation surpasses the threshold of the neuron it will depolarize and send an electrical signal down the length of its axon, thereby passing the message along to a distant neuron. If the stimulation is insufficient, no message will be sent. An analogy for thresholds: a sleeping person may not stir at all in response to quiet sounds, but a loud sound will awake them completely. If the thresholds for your afferent nociceptors are lowered, your experience of pain becomes akin to the hypersensitivity of a shallow sleeper.

The same cytokines mentioned in the above article (IL-1β and TNFα) can also enter the cerebrospinal fluid and lower the threshold of nociceptors in the spinal cord. This means that when a nociceptor in the periphery (e.g. skin or muscle) sends a message to a nociceptor in the spinal cord, that second nociceptor is more likely to pass that message along to the brain, where it is likely to be interpreted as pain.

The inflammatory milieu surrounding the nerve terminals in the skin contains numerous inflammatory mediators during CHS (Kondo et al., 1994; Westphal et al., 2003; Christensen and Haase, 2012), such as tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β), which may be retrogradely transported to cell bodies of dorsal root ganglion neurons and contribute to the increased Na+ currents observed in this study. Indeed, TNFα and (IL-1β) have been demonstrated to augment TTX-sensitive and TTX-resistant Na+ currents in nociceptive dorsal root ganglion neurons (Binshtoket al., 2008; Czeschik et al., 2008).

(The dorsal root ganglion is the part of the spinal cord that relays pain signals. Na+ currents are electrical signals sent along axons. Axons are like long cables transmitting information from neuron to neuron.)

To add to the misery, it appears that long-term inflammation can alter the receptors on neurons, such that they remain hypersensitive even after proinflammatory cytokines are no longer present:

Following inflammation of the hindpaw, myelinated, CGRP-positive neurons projecting to the paw skin displayed elevated mechanical currents in response to mechanical stimuli. Conversely, muscle inflammation markedly amplified mechanical currents in myelinated, CGRP-negative neurons projecting to muscle. These data show, for the first time, that mechanically gated currents are amplified following in vivo tissue inflammation, and also suggest that mechanical sensitization can occur in myelinated neurons after inflammation.

Mechanical stimulation? Touch and pressure are forms of mechanical stimulation. This mechanical sensitization may therefore partly explain the presence of tender points in fibromyalgia sufferers. Incidentally, though my burning/aching pain is in remission, I still have the tender points. This dovetails with the notion that prolonged inflammation leads to physiological changes that persist even after the inflammation subsides.



 In future posts I'll explore:
 - how peripheral sensitization can lead to central sensitization
 - potential causes of inflammation in fibromyalgia
 - strategies to reduce inflammation
 - biomarkers for inflammation (e.g. blood tests)
 - other inflammatory conditions that are often comorbid with fibromyalgia (e.g. IBS, ME/CFS, Major Depression, and bipolar disorder)


Footnotes:
*1 'Efferent' is the term for signals sent outwards from the brain.

Sources:

The sympathetic nervous response in inflammation

http://arthritis-research.biomedcentral.com/articles/10.1186/s13075-014-0504-2

Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959553/

Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478256/

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7/29/16 Addenda:

I just found out about the Fibro Friday link up over at http://www.fibrobloggerdirectory.com/ , a great repository of FMS blogs and resources. I'll be sharing this post there for anyone interested in the biomolecular interactions in fibromyalgia.

A few more studies to look into (for the biomechanically-minded):

NLRP3 inflammasome is activated in fibromyalgia: the effect of coenzyme Q10.

http://www.ncbi.nlm.nih.gov/pubmed/23886272

MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study.

http://www.ncbi.nlm.nih.gov/pubmed/21714842

Aaand, footage of me burning myself repeatedly with matches to demonstrate that it hurts very little in comparison to fibromyalgia. Skip to 3:30 for the worst burn and a brief explanation of cytokines and nociception.

https://www.youtube.com/watch?v=iX1Vgl0GCKQ