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

Discussion in 'Latest ME/CFS Research' started by voner, Oct 8, 2013.

  1. lansbergen

    lansbergen Senior Member

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    http://ajpregu.physiology.org/content/283/2/R287
    Over expression could explain the constipation I get at the beginning of a flare up.
  2. lansbergen

    lansbergen Senior Member

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    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.

    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/

    [​IMG]
    voner and Emootje like this.
  3. Snow Leopard

    Snow Leopard Senior Member

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    edit - updating, got some wikipedia links confused

    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):

    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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  4. lansbergen

    lansbergen Senior Member

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  5. Snow Leopard

    Snow Leopard Senior Member

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    lansbergen You are right. Seems to be a case of mistaken identity. ;)
    Updating my post now.
  6. Valentijn

    Valentijn Activity Level: 3

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    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?
  7. voner

    voner Senior Member

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    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?
  8. Valentijn

    Valentijn Activity Level: 3

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    Yeah, they said the CFS+FM results were pretty much the same as the CFS results:
  9. Valentijn

    Valentijn Activity Level: 3

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    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.
  10. voner

    voner Senior Member

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    How about any mention of orthostatic intolerance or POTS???
  11. Valentijn

    Valentijn Activity Level: 3

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    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.
  12. Dolphin

    Dolphin Senior Member

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    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.
  13. Dolphin

    Dolphin Senior Member

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    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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  14. Valentijn

    Valentijn Activity Level: 3

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    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
  15. Dolphin

    Dolphin Senior Member

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    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

    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:
    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.
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  16. Snow Leopard

    Snow Leopard Senior Member

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

    voner Senior Member

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

    [​IMG][/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.....
  18. Valentijn

    Valentijn Activity Level: 3

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    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.
  19. lansbergen

    lansbergen Senior Member

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    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.
    Valentijn likes this.
  20. Gijs

    Gijs

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    Valentijn likes this.

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