“Key transducers of nociception and pain”

Much of the activity in nerve cells is regulated by very small channels that regulate the flows of ions such as calcium, sodium and magnesium in or out of the cells.

Given the central nervous system problems in ME/CFS and FM and the clear role ion channels in producing increased sensitivity to pain and stimuli, they would seem to be an obvious target for researchersl This study, though – from the NCNED Australian group – is the first to concentrate on them in ME/CFS.

ion channel

Ion channels control the flow of ions into a cell. The ion channels examined in this study mostly affect nerves.

The ion channels examined in this study – the TRP channels –  were recently called the “key transducers of nociception and pain”. (Neurons associated with the vagus nerve also contain many TRP ion channels.)

These channels trigger cells to respond to changes in their environment caused by pathogens, oxidative stress, chemicals, toxins and pH.  These  ion channels can be activated by numerous inflammatory by-products including toxins, cytokines and irritants.

Given the wide range of substances these ion channels react to having them bug out on you could lead to a lot of problems.  Some researchers think the nervous system in ME/CFS and FM patients is over-reacting to stimuli. If it is it could start here.

Super sensitive ion channels could send pain and sensory signals coursing along the nerves to the brain at the slightest provocation. Translated into pain and other stimuli this barrage of sensory signals could hamper your ability to focus and think.

This study didn’t actually test ion channels; they looked for single nucleotide polymorphisms (SNP’s) in the genes governing how these ion channels function. SNP’s are very small changes in the genes that can alter how proteins and ultimately cells function. Some SNP’s produce no  change (are benign), while others alter gene transcription in fundamental ways that produce physiological changes in how nerve and other cells function.  For instance a SNP could cause an ion channel to open a bit more quickly in response to some stimulus thus telling the nerves to send pain or other signals more quickly to the brain.

Many SNP’s have been associated with diseases.

The Study

Immunology and Immunogenetics Insights 2015:7 1 Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients Sonya M. Marshall-Gradisnik1,2, Peter Smith2, Ekua W. Brenu1,2, Bernd Nilius3, Sandra B. Ramos1,2 and Donald R. Staines. 1. School of Medical Science, 2. The National Centre for Neuroimmunology

The Australian group examined 240 SNP’s in 21 genes governing TRP ion channel         functioning (over ten per gene on average) in 115 people with chronic fatigue syndrome and 90 healthy controls.


“These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.”

In studies like this you hope to have some SNP’s show up but what you really hope to see are SNP’s concentrated in a couple of  genes. Finding SNP’s concentrated in a couple of genes would suggest those genes are bad shape; bad enough shape to possibly contribute to disease.

That’s exactly what this study found. It found 13 small gene alterations nine of which were found in one of the 21 genes tested (TRPM3) and four of which were found in two other genes TRPC4/ TRPAI).

bulls-eye chronic fatigue

With most gene alterations occurring in just three genes – the study hit a nice bulls-eye.

The results were close to being even more pinpoint.  A fourteenth polymorphism that just barely missed significance (p<.051) was also associated with TRPM3 and two more polymorphisms for TRPA1 and TRPC4 (p<.065 / p< .068) were on the edge as well.

This is the second rather shockingly specific finding in the last year.  The Stanford MRI study that found that almost all of the ME/CFS patients had alterations in a very, very small part of the brain (which none of the controls did) was the other.  We rarely see such  pinpoint results in ME/CFS.

The Genes

Two of the suspect ion channels are “thermosensory channels”  (thermoTRP’s) that are activated by changes in temperature – putting a spotlight possibly on inflammation and thermoregulation.  Studies indicate that the appearance of these channels in the sensory neurons is closely associated with the appearance of pain. Because they integrate several signaling pathways drug development to block them from functioning is being actively pursued.


The TRPC genes play important roles in memory, attention, sensory acuity, emotion, pain, and motor control in the amygdala, entorhinal cortex, hippocampus, and prefrontal cortex. The specific TRPC gene highlighted in this study – TRPC4 – can affect intestinal functioning and smooth muscle contraction.


TRPA1 regulates the activity of sensory neurons. Nerve fibers containing TRPA1 densely innervate the skin, airways and gastrointestinal tract. Pro-inflammatory and pain producing agents such as bradykinin, histamine, prostaglandins, and trypsin can all activate TRPA1.  Once activated TRPA1 prompts the nerves to produce more pain and more inflammation.  A super sensitized gene like TRPAI could go far to explain the pain problems in ME/CFS.  The TRPA1 ion channel is a key player in the production of headaches and migraines.

TRPAI also interacts with the rather notorious TRPVI  gene that has been implicated in migraine and other pain conditions. The two are so closely connected that it’s possible that a balky TRPAI ion channel could affect TRPV1 channels. Increased levels of  TRPV1 receptors popped up  in ME/CFS patients after exercise in one of the Light’s studies.

The TRPV1 channel is widely distributed in neuronal as well as non-neuronal tissues. In the peripheral nervous system, TRPV1 is highly expressed in a hangout place for herpesviruses – the dorsal root (DRG)  ganglia which are implicated in  pain sensitization.  TRPV1 is over-expressed in several chronic pain conditions such as rheumatoid arthritis, osteoarthritis, bone cancer-induced pain and several neuropathies.


The lion’s share of polymorphisms  were found in the TRPM3 gene.  The most recently described and least well known TRP gene, TRMP3 was uncovered when it was found that the steroid pregnenolone sulfate activated it.  Pregnenolone is the precursor to the mineralcorticoids, glucocorticoids, androgens and estrogens. It triggers the TRMP3 ion channels in the brain cells to release glutamate – an excitatory neurotransmitter.

TRPM3 ion channels have been implicated in inflammatory pain syndromes as well as rheumatoid arthritis, and the secretion of pro- inflammatory cytokines.

This channel’s ability to regulate insulin/glucose intake could impact metabolic functioning.  Another intriguing function of this channel is to induce contractions of the smooth muscles than line the blood vessels and other areas. TRPM3 is not that well known yet, but it’s clear it plays an important role in detecting noxious stimuli in healthy and inflamed tissue and research  is growing.


Sonya Marshall Gradisnuk

Sonya Marshall Gradisnuk leads the NCNED team that produced these findings.

Such specific findings are both unusual and gratifying in ME/CFS. They suggest the researchers are on the right track.  While the findings in this paper need to be replicated, for now, at least, there’s  no muddiness – no need to strain at putting together some scenario that might work. There’s just the rather eye-popping finding that nine (almost ten)  of the 13 gene alterations found significantly more often in ME/CFS patients in Australia were concentrated in just one of twenty-one genes examined.

It’s a bit unfortunate those genetic alterations occurred in one of the more recently described and less well known ion channels (TRPM3) but research into this ion channel is growing. (A recent study uncovered a substance able to open TRPM3 ion channels much more quickly than pregnenolone. That substance will be used to better understand TRPM3 ion channels. The finding indicated that TRPM3 activation contributes to neurogenic inflammation.)

What could be happening with these ion channels and ME/CFS?  A tendency for them to genetically be set on a hair trigger could perhaps explain the many and often overwhelming sensory sensations (pain, fatigue, problems with stimuli) found in the disorder.

Drug companies are reportedly eagerly pursuing drugs that alter the function on these ion channels.


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