Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome - Mar 2019 - Yasui et al

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome
Abstract
Background

Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.

Methods
Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity.

Results
The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.

Conclusion
Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.
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https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1456-x

Personally I do not like this 'rat model' of CFS, I don't think there is anyway that they can say that the rat is suffering from CFS after what they do to achieve it. Thus, IMO, making the whole thing incredibly cruel and futile.
 
If they 'know' how to diagnose CFS in a rat why don't they know how to do it in a 'human'?

I'm fairly sure that systematically torturing animals is probably not the way forward. Why do i say torturing? Because deliberately inflicting pain in a high stress environment is generally what the word means.
 
The current rodent models of ME/CFS are ridiculous, and seem to bear no relation to ME/CFS.

When we create murine models of chronic coxsackievirus B myocarditis, which are useful models, we will actually infect the mouse heart with this virus. Why not try to create a murine ME/CFS model by infecting the mouse brain with coxsackievirus B?
 
Jonathan Edwards said:
That sounds just as pointless and barbaric to be honest.
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Three brain post mortem studies on ME/CFS patients showed enterovirus infection in the brain, whereas 8 controls who did not have ME/CFS had no enterovirus in the brain.

Now of course the statistical significance is not high; that's due to the difficulty in getting brains to study. But a viral brain infection model I think is worth a try.

Yet to my knowledge nobody has tried to create an ME/CFS mouse model by setting up a chronic enterovirus brain infection.

A few years ago I wrote to enterovirus virologist Prof Ralph Feuer about the possibility of creating coxsackievirus B brain infection murine model of ME/CFS. This is an excerpt from his reply:
CVB might be utilized to establish a murine version of disease, although finding funding is the main difficulty. Funding from NIH is a crapshoot – I can spend 3 months writing a competitive grant on the subject, and obtaining funding is like winning the lottery (with lottery odds). I have contacted Enterovirus Foundation for funding information…but no response.

Most likely, neurons/neuron progenitor cells support greater levels of CVB infection than astrocytes (at least in vivo)..although both targets could contribute to the disease process. Chronic infections, including those caused by CVB, could lead to the chronic activation of those cytokines mentioned, as well as others, with unknown consequences.
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My lab has actually established a neonatal murine model of CVB infection in the CNS (some relevant PDFs attached). Our model has documented infection of myeloid cells and neural progenitor cells, establishment of persistent infection in the CNS, and chronic inflammation in the hippocampus and entorhinal cortex. Our unpublished data suggest a reduction in resident progenitor cell number and behavioral alterations/memory deficits (using Morris Water Maze) into adulthood. Unfortunately, obtaining grant funding to continue the work has proved difficult.
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But the murine brain is not the only organ that you might experimentally target with an infection. We know that several autopsies have shown dorsal root ganglia (DRG) inflammation in ME/CFS, so you could also try to see what happens if you infect the DRG.
 
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from the text:
Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.
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means, resting helped the mice.

chicken or egg ?
- pain promotes negative emotions
or
- negative emotions promoting pain ?

Emotions can evoke strong reactions that have profound influences, from gross changes in our internal environment to small fluctuations in facial muscles, and reveal our feelings overtly. Muscles contain proprioceptive afferents, informing us about our movements and regulating motor activities

however, it is unknown if emotional processes can modulate muscle feedback. Presently, we explored whether muscle afferent sensitivity adapts to the emotional situation.

We found that muscle afferent firing was modified by the emotional context, especially for sad emotions, where the muscle spindle dynamic response increased. We suggest that this allows us to prime movements, where the emotional state prepares the body for consequent behaviour-appropriate reactions.

https://www.nature.com/articles/s41598-017-08721-4

Aix Marseille Univ, CNRS, LNIA, FR3C, Marseille, France
Rochelle Ackerley, Jean-Marc Aimonetti & Edith Ribot-Ciscar
Department of Physiology, University of Gothenburg, 40530, Göteborg, Sweden
Rochelle Ackerley
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what if mecfs patients were hypnotized?

you will be feeling no pain, no fatigue ...

then, they are sent on an exertion parcours.

back to non-hypnosis - would they show PEM ?
 
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John Mac said:
Maybe this is the childhood abuse the BPS crowd are convinced we all suffered, but we've all erased the painful memory of being trapped in a cage.
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Painful memories?

You know where you are in a cage, you know how things stand.

You know your place in the scheme of things and most of your previous problems become meaningless/irrelevant.

Constant uncertainty causes stress and unhappiness, so it follows that certainty is a path to happiness :whistle:

(Why do you think people keep going back to prison? Or why the decision to exist in a small wooden box underground is rarely changed? Certainty, a much undervalued thingymabob.)
 
Although I am not keen on the use of animals, I would be curious to know what the effect would be if an ME patients blood (or the serum) were introduced into a mouse or similar; ie if the same 'changes' are effected as in Ron Davis and also Fluge and Mellas test.
 
Marky said:
You can`t give rats ME when we have no idea what it is.. Pointless and cruel research
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It seems we may now have the technology to actually do this, if it's in the red stuff, and that thing makes the non red bits go nuts and have ME, a simple transfer of that thing should do it.

Of course the rats would then probably have ME, but as they couldn't read, understand the local language, follow simple instructions on how to operate a washing machine or hold a very interesting conversation beforehand what difference would it make, that would be applicable? I mean the physical limitations imposed by ME are unlikely to have a huge impact on an animal that lives in a foot long perspex box and hardly ever has to cook, so that's no help either.

How would you tell when you'd 'cured' them?
 
Wonko said:
It seems we may now have the technology to actually do this, if it's in the red stuff, and that thing makes the non red bits go nuts and have ME, a simple transfer of that thing should do it.

Of course the rats would then probably have ME, but as they couldn't read, understand the local language, follow simple instructions on how to operate a washing machine or hold a very interesting conversation beforehand what difference would it make, that would be applicable? I mean the physical limitations imposed by ME are unlikely to have a huge impact on an animal that lives in a foot long perspex box and hardly ever has to cook, so that's no help either.

How would you tell when you'd 'cured' them?
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Maybe you’d know if they weren’t up all night on rats4ME forum
 
Wonko said:
It seems we may now have the technology to actually do this, if it's in the red stuff, and that thing makes the non red bits go nuts and have ME, a simple transfer of that thing should do it.

Of course the rats would then probably have ME, but as they couldn't read, understand the local language, follow simple instructions on how to operate a washing machine or hold a very interesting conversation beforehand what difference would it make, that would be applicable? I mean the physical limitations imposed by ME are unlikely to have a huge impact on an animal that lives in a foot long perspex box and hardly ever has to cook, so that's no help either.

How would you tell when you'd 'cured' them?
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I think we would have to know where in the disease mechanism chain whats apparently in the blood is, for such an experiment to potentially be useful. And even then, as u point out, its difficult to make sense of any potential symptoms in rats, and compare, due to the fact that they are not exactly human.

I feel like a lot of research that`s being conducted is more grounded in researchers needing something to do, more than genuinely trying to figure out what`s going on (like with Ron Davis & co and Fluge & Mella).
 
I think, and hope, that the last para of your post may be unfair.

I suspect that what's happening is researcher thinks "this looks like an interesting thing to study, how can I use what I have, rats, rat wranglers, and such and such drugs and tests, to do something useful", whilst not understanding anything about ME.

So obviously the research is unlikely to be terrifically useful.

But this is not really down to the researcher wanting an ME based grant, it's down to almost no one having any understanding of what ME is.

Which is why we need the research after all.

So not entirely their fault.
 
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