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    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

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new Alan Light paper... alpa-2a, glutocorticoid implication

lansbergen

Senior Member
Messages
2,512
http://www.ncbi.nlm.nih.gov/pubmed/15078339
The effects of the alpha2-adrenergic receptor agonists clonidine and rilmenidine, and antagonists yohimbine and efaroxan, on the spinal cholinergic receptor system in the rat.

Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as alpha2-adrenergic receptors.

Increased alpha2 adrenergic repectors decreases acetylcholine release. That makes pain more intense.

That could explain my need for smoking and levamisole. The pain was unbearable and is almost gone now.

http://pharmacologycorner.com/alpha-receptors-1-2/

alpha_2_receptors.gif
 

Snow Leopard

Hibernating
Messages
5,902
Location
South Australia
edit - updating, got some wikipedia links confused

Does the AD2A cause the abnormal inflammation itself?

http://en.wikipedia.org/wiki/Alpha-2A_adrenergic_receptor
http://en.wikipedia.org/wiki/Alpha-2_adrenergic_receptor
http://en.wikipedia.org/wiki/Alpha-adrenergic_agonist

General effects of Alpha-2 adrenergic receptors (from Wikipedia):

General

Common effects include:

The first bolded point leads to the latter bolded point. The inhibition of lipolysis is interesting in the context of fatigue. A high level of free fatty acids (as a result of lipolysis) is associated with central fatigue.

(more TBA)

RNase L plays a role, which is interesting too.

http://www.jbc.org/content/280/47/38898.full

The previous Light studies are interesting though, one noted that FM patients had a drop in the adrenergic receptors, whereas the CFS patients had the increase seen in this study.
http://phoenixrising.me/archives/5790

They also discussed this in a presentation:
Offer Presentation 2-3-2011.pp

And the MS/CFS study:
http://europepmc.org/articles/PMC3256093/reload=0;jsessionid=nCtmWZg3gfjAMQZo9pff.40
 
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15,786
General effects of Alpha-2 adrenergic receptors (from Wikipedia):
So it looks like that would explain my chronically low norepinephrine levels, and hypotension.

My GI tract also seems to shut down during a crash ... basically two days or so where nothing comes out, and I get really nauseous if I try to eat much of anything. Though come to think of it, my GI tract is always a bit slow - but I take magnesium every day to keep things moving.

I also don't seem to be capable of burning fat under any circumstances now. Maybe if I'm inactive enough for a while, so the increased AD2A isn't triggered?
 

voner

Senior Member
Messages
592
Valentijn,

Did the authors discuss the patients with fibromyalgia and the patients without fibromyalgia in reference to the Alpha 2a receptor phenom that Snow Leopard mentioned?
 
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15,786
Did the authors discuss the patients with fibromyalgia and the patients without fibromyalgia in reference to the Alpha 2a receptor phenom that Snow Leopard mentioned?
Yeah, they said the CFS+FM results were pretty much the same as the CFS results:
The three CFS patients with comorbid fibromyalgia were similar to CFS only patients on all mRNA measures and symptom measures; therefore, analyses were conducted including these patients in the CFS group. This is consistent with previous work shoving no difference in expression changes following exercise between CFS patients with and without comorbid fibromyalgia.
 
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15,786
It sounds like the GG version of the rs553668 SNP on the ADRA2A ("AD2A" in the study) gene is associated with increased gene expression, as well as increased risk of Type 2 Diabetes due to slowed glucose release. It's an extremely common version in Europeans (pretty much everyone has it) though less common in other ethnic groups.

http://omim.org/entry/104210#0001 has a little info about it.
 
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15,786
How about any mention of orthostatic intolerance or POTS???
I don't see it mentioned, and the study seems to only look at pain, fatigue, confusion and mood compared to gene expressions. But as Snow Leopard mentioned above, overexpression of the gene is known to cause OI in the form of hypotension. The tachycardia in POTS might be the response to the low BP in some cases - mine certainly shoots up when my blood pressure or pulse pressure is low.
 

Dolphin

Senior Member
Messages
17,567
I've read the full paper now, and it looks like they did a really good job of controlling for various variables, though it is a small study (13 patients, 11 controls) and uses Fukuda (any boldings and typos are mine):

I'm impressed that they managed to control for fitness levels, which presents a pretty strong argument against any changes being due to deconditioning. They also took a close look at all of the peak exercise data, and the only significant difference was in perceived pain - hence both groups were performing similarly to each other.
The only difference was in RPE=Rating of Perceived Exertion.

My impression is that is a pretty consistent finding across studies: match everything else up and the patients with ME/CFS have a higher RPE.
 

Dolphin

Senior Member
Messages
17,567
This paper also contained a brief discussion of other research into NR3C1 in CFS, from a genomic standpoint:
Recently, polymorphisms in the NR3C1 receptor have been studied in CFS patients to investigate HPA axis abnormalities. Both Rajeevan et al. and Smith and colleagues found a number of mis-sense mutations that occurred more frequently in severely ill CFS patients than in controls or in relatively well CFS patients (rs1866388, rs2918419, rs860458, rs852977, rs6188, and rs258750).

Oddly, it's the major alleles of those SNPs which are more associated with risk (I'm homozygous for all of the minor alleles, which is pretty rare). And none of them are listed as missense mutations, which is rather confusing. But it looks like Unger is involved in that study, so it's probably got a bunch of non-ME patients.

And one of the studies claims to attribute genes to 76% of the risk of getting CFS, which seems a bit unlikely. I need to take a closer look at all three of the studies cited:

[34] Rajeevan MS, et al. Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav. 2007 Mar;6(2):167-176.
[35] Smith AK, et al. Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue. Pharmocogenomics. 2006 Apr;7(3):387-394.
[36] Goertzel BN, et al. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. 2006 Apr;7(3):475-483.
These three studies are all CFS (empiric criteria) studies, which I think are almost useless.

And they are all on the same (Wichita) cohort of patients (the CDC took patients in for two days in 2003 (processed, I think started at the very end of 2002); with the data they got different teams to look at it and see what they came up with )
 
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15,786
And they are all on the same (Wichita) cohort of patients (the CDC took patients in for two days in 2003 (processed, I think started at the very end of 2002); with the data they got different teams to look at it and see what they came up with )
Ah, they really are useless studies then ... wasn't the Witchita cohort based on pretty much asking people if they think they might have chronic fatigue? :p
 

Dolphin

Senior Member
Messages
17,567
Dolphin said:
And they are all on the same (Wichita) cohort of patients (the CDC took patients in for two days in 2003 (processed, I think started at the very end of 2002); with the data they got different teams to look at it and see what they came up with )
Ah, they really are useless studies then ... wasn't the Witchita cohort based on pretty much asking people if they think they might have chronic fatigue? :p
Well initially they were screened by telephone calls. However I don't think that's the problem. It's a long story - a lot of info has been collated on it on this petition website: http://www.ipetitions.com/petition/empirical_defn_and_cfs_research/index.html

Here's part of the definition
We used information from the SF-36, MFI and Symptom Inventory to classify subjects empirically according to the 3 main dimensions of CFS: functional impairment (SF-36), fatigue (MFI) and accompanying symptoms (Symptom Inventory). We defined substantial reduction in occupational, educational, social, or recreational activities as scores lower than the 25th percentile of published US population [11] on the physical function (≤ 70), or role physical (≤ 50), or social function (≤ 75), or role emotional (≤ 66.7) subscales of the SF-36. We defined severe fatigue as ≥ medians of the MFI general fatigue (≥ 13) or reduced activity (≥ 10) scales. Finally, subjects reporting ≥ 4 symptoms and scoring ≥ 25 on the Symptom Inventory Case Definition Subscale were considered to have substantial accompanying symptoms.

The "role emotional" subscale of the SF-36 is about not doing much because of your mood.

Then one could be counted as having chronic fatigue if you had reduced activity. People could have reduced activity due to depression, for example.

One study found that 38% with major depressive disorder satisfied the empirical criteria:
Jason, LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control's empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies 2008, doi:10.1177/1044207308325995.

The CDC previously found a prevalence of 235 per 100,000 in a telephone study using the Fukuda definition.
Using almost the exact same methodology, using the empiric criteria (which they call a version of the Fukuda criteria), the prevalence was nearly 11 times higher 2540 per 100,000.

Probably contains all sorts of people with full depression, as well as other people with a bit of depression who are also unhealthy, etc. as well as "proper" CFS cases.
 

Snow Leopard

Hibernating
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5,902
Location
South Australia
These three studies are all CFS (empiric criteria) studies, which I think are almost useless.

And they are all on the same (Wichita) cohort of patients (the CDC took patients in for two days in 2003 (processed, I think started at the very end of 2002); with the data they got different teams to look at it and see what they came up with )

Regardless of the criteria, none of the results were indicative of anything, at least in my opinion.
 

voner

Senior Member
Messages
592
http://pharmacologycorner.com/alpha-receptors-1-2/

alpha_2_receptors.gif
[/quote]

Snow Leopard and lansbergen,

Give me some help on my speculation here, please. Speaking specifically about the Alpha receptors, would one want to damp down the receptor response by using a antagonist? If so, then that would increase acetylcholine and norepinephrine, correct? Any spec speculation on what else an antagonist might do?

For me personally, it would be great to increase acetylcholine which is associated with the parasympathetic system also. A decade to 15 years ago I was using the drug, Mestinon, which is a parasympathetic boosting pharmaceutical. This was in the days before I had a clue as to what was going on in my body, but I happened to notice that I did not have nearly as much postexertional malaise after exercise and kept using this drug specifically because of this that. I used to call it, "I don't have as much kickback next day or the day after after exercise". In those days I did not know that the term "postexertional malaise" existed.

Anyway, it looks like an available alpha 2a receptor antagonist is Yohimbine. .... From the already psychopharmacology webpage is this description:

.....Yohimbine blockade of alpha 2 receptors leads to increased release of norepinephrine with susequent stimulation of cardiac beta 1 receptors and peripheral vasculature alpha 1 receptors.....
 
Messages
15,786
Give me some help on my speculation here, please. Speaking specifically about the Alpha receptors, would one want to damp down the receptor response by using a antagonist? If so, then that would increase acetylcholine and norepinephrine, correct? Any spec speculation on what else an antagonist might do?
Yes, an antagonist should help in diminishing the up-regulation of the ADRA2A gene.

I started Yohimbe about two weeks ago, which is the most potent and specific antagonist of ADRA2A. I have chronically low norepinephrine, and was taking an NRI to deal with my orthostatic intolerance for the past year. When switching to Yohimbe, my OI stayed under control, plus I seem to have had no PEM, despite spending about 14 hours in airports and on an airplane.

Gut motility has also improved, to the extent that I had to cut back my magnesium, yet don't have any of the muscle twitching and such I'd usually get with less magnesium. Theoretically, it should also help with lipolysis, which can be suppressed by ADRA2A.

I haven't had any side effects thus far, and no signs of needing to increase my dosage. If anything, the effects seem to be more constant now, possibly due to norepinephrine levels rising in general? But its actions should be very specific for ADRA2A, ADRA2B, and ADRA2C, unlike the less powerful pharmaceutical ADRA2A antagonists, which also have a significant or even larger effect on a histamine receptor, HTP receptors, etc.
 

lansbergen

Senior Member
Messages
2,512
voner
Valentijn is the guinea pig. So far so good,

Nicotine can replace acetylcholine on the nicotine acetylcholine receptors.

I use an a7nAchR modulator and smoke like a chimey. It helped me a lot. Improvement is slow but steady. I am not cured yet but compared to what it was when I started it I went from hell to heaven.