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Ponderings and speculations about purinergic signaling, in pursuit of a unified ME/CFS theory

Discussion in 'General ME/CFS Discussion' started by necessary8, Oct 29, 2017.

  1. Jesse2233

    Jesse2233 Senior Member

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    Fascinating @necessary8! Really enjoying reading your thought process, it’s great how many connections between existing studies and symptoms you’re making, and from my laymen’s standpoint it all sounds good. I also appreciate your ambivalence, that’s how good hypotheses should be framed. Thanks for compiling this and hopefully your recovery doesn’t take too long

    Would be great to get Light’s thoughts on all this (in addition to Davis and Naviaux). Maybe he has unpublished data he could share, or could quickly test some of the metabolite combos you’re interested in. I know he’s open to correspondence as he’s answered questions on mtDNA I’ve asked him in the past.

    How does this play into PEM caused by cognitive or emotional exertion? Those aren’t exactly micro-injuries although they do involve stress and presumably alterations in physiology

    What about neuronal antibodies? I’m thinking of the anti-D1/D2 Abs seen in PANS and the anti-NMDR Ab seen in Autoimmune Encephalitis

    Also there’s the possibility of a leaky blood brain barrier (perhaps damaged by infection or chemical exposure) as you alluded to with endothelial dysfunction

    Going to embarrass myself by bringing up HBOT and the benefits reported by CFS patients receiving it anecdotally and in two studies (one by Meirlier, one by Turkish researchers). HBOT drastically increases the amount of dissolved oxygen in plasma, and under Naviaux’s model wouldn’t that make the dauer state much worse? FWIW I emailed Naviaux on HBOT but did not hear back

    No rush in responding, and again great work!
     
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  2. debored13

    debored13 Senior Member

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    the niacinamide result is particularly interesting, tho do you think that would be explained by smoking as well? I wonder how much one can megadose niacinamide
     
  3. debored13

    debored13 Senior Member

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    I think I found something relevant to a very small part of this theory.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489427/ (I believe you posted this paper later in the thread showing the connection between neuropathic pain, microglia, and purinergic signalling).
    "Nerve injury often causes debilitating chronic pain, referred to as neuropathic pain, which is refractory to currently available analgesics including morphine. Many reports indicate that activated spinal microglia evoke neuropathic pain. The P2X4 receptor (P2X4R), a subtype of ionotropic ATP receptors, is upregulated in spinal microglia after nerve injury by several factors, including CC chemokine receptor CCR2, the extracellular matrix protein fibronectin in the spinal cord, interferon regulatory factor 8 (IRF8) and IRF5. Inhibition of P2X4R function suppresses neuropathic pain, indicating that microglial P2X4R play a key role in evoking neuropathic pain."

    I found this paper: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962576/ which discusses the use of Low Dose Naltrexone in pain conditions and speculates extensively on its role in reducing inflammation via microglia and TLR4.

    "Anti-inflammatory effects of LDN in vivo and in vitro
    In describing LDN’s clinical utility, it is important to understand the dual physiologic mechanisms of naltrexone and other opioid antagonists. Most clinicians are familiar with naltrexone as a potent and nonselective opioid receptor antagonist and treatment for opioid addiction. Naltrexone, at typical dosages, significantly blocks activity at mu- and delta-opioid receptors as well as (to a lesser extent) kappa-opioid receptors [16]. Because beta-endorphin activity at mu-opioid receptors is associated with endogenous analgesic processes, it may seem counterintuitive to administer naltrexone to individuals with chronic pain, as we might expect the medication to reduce analgesia produced by beneficial endogenous opioid activity.

    Naltrexone, however, exerts its effects on humans via at least two distinct receptor mechanisms. In addition to the antagonist effect on mu-opioid and other opioid receptors, naltrexone simultaneously has an antagonist effect on non-opioid receptors (Toll-like receptor 4 or TLR4) that are found on macrophages such as microglia [17]. It is via the non-opioid antagonist path that LDN is thought to exert its anti-inflammatory effects. Microglia are central nervous system immune cells that are activated by a wide range of triggers [18]. Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise [19]. When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects [20]. Given the wide variety of inflammatory factors produced by activated microglia (e.g., proinflammatory cytokines, substance P, nitric oxide, and excitatory amino acids)" (guessing that glutamate may be included here?) "[21], a range of symptoms and medical outcomes could share the pathophysiological mechanism of central inflammation. Conditions such as fibromyalgia may involve chronic glial cell activation and subsequent production of proinflammatory factors. The hypothesis is indirectly and partially supported by the high degree of symptomatic overlap between fibromyalgia and cytokine-induced sickness behaviors.

    Both naloxone and naltrexone have been demonstrated to exert neuroprotective and analgesic effects [22]. The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited [23]. By suppressing microglia activation, naloxone reduces the production of reactive oxygen species and other potentially neuroexcitatory and neurotoxic chemicals [24]. The anti-inflammatory effect of opioid antagonists may also extend to the periphery, as evidenced by suppressed TNF-alpha, IL-6, MCP-1, and other inflammatory agents in peripheral macrophages [25]. It should be noted that most animal work has used naloxone, while most human work has used naltrexone (because of its higher oral availability). We cannot discount the possibility that findings from one compound would imperfectly translate to the other.

    The hypothesis that naltrexone and naloxone operate via glial cells to exert their beneficial actions is supported by work with dextro-naltrexone. Dextro-naltrexone is a stereoisomer of naltrexone which is active at microglia receptors but has no activity on opioid receptors [26]. Dextro-naltrexone possesses analgesic and neuroprotective properties [27]. Therefore, the analgesic, anti-inflammatory, and neuroprotective effects of naltrexone do not appear to be dependent on opioid receptors.

    The majority of work to date has focused on naloxone/naltrexone’s action on microglia TLR4 (e.g., [28]). However, it should be mentioned that the data do not perfectly fit a TLR4 hypothesis [29], and other targets have been proposed, including astrocytes [30] and NADPH oxidase 2 [31]. Other sites of action, including the opioid growth factor receptor (OGFr) [32], are being discovered, raising even more potential mechanisms of action. Given the multiple and varied sites where naltrexone exhibits significant pharmacologic activity, it will be difficult to determine with certainty the paths that are critical for the clinically beneficial effects. This area of research is being vigorously pursued by multiple laboratories."


    I'm not at the point where I can understand your whole theory on purinergic signalling but I do believe this might be relevant!!
     
  4. debored13

    debored13 Senior Member

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    in the conclusion of the paper, under the section "Disadvantages of LDN" they state:
    "Lack of proper dosage-finding experiments
    It is highly probable that 4.5 mg is not the optimal dosage for all individuals with fibromyalgia, as it is rare for any pharmaceutical to have a one-size-fits-all dosage. In addition to obvious variables such as body mass index, individuals may differ in their metabolism, opioid receptor sensitivity, or microglia sensitivity to LDN. It is plausible that individuals who do not respond to 4.5 mg daily may respond to either lower or higher dosages. Other dosing schedules, such as twice a day, have not been explored in clinical studies. For now, the once daily 4.5-mg dosing schedule appears to be used without much critical analysis, as there are no published reports of even basic dose-ranging in human participants. Proper dosing studies need to be performed to determine the therapeutic range of the drug and to identify a process for determining an individual’s optimal dosage. The importance of determining proper dosing strategies is highlighted by animal research that suggests, for example, that while LDN may suppress tumors when used in the typical fashion, it may actually enhance tumor growth when administered more frequently [48].

    No hard data on long-term safety
    Even though naltrexone has a long history of safe use with a wide range of large dosages, we know very little about the long-term safety of the drug when used chronically in low dosages. The low dosage is often cited as a reason for clinicians and patients to not be concerned about safety. However, we must be open to the possibility that the unique clinical effects possible with the low dosage could also present new health risks. There are no reported serious concerns to date. While inhibition of immune system parameters could theoretically raise the risk of infections or cancer due to decreased immunosurveillance, there have been no reports of such a side effect at any dosage of naltrexone."


    This is something I want to bring up--I feel like we'd have better data and better anecdotal evidence on LDN if people knew which dose would be effective for them when they start. There are people who feel better from LDN, and then there is a whole 'nother group which seems like they (quite understandably, mind you) quit early on due to not being able to tolerate the side effects.
    I have been giving it a go recently again and while it's not a wonder drug, it is the only thing that has allowed me to even do things like read the above...
     
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  5. debored13

    debored13 Senior Member

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    So one caution I'm telling myself about my enthusiasm is that this paper has a lot of disclaimers that some of it is just speculation and that it may not work via the mechanism they propose. But I do think their theory is sound and that more research on Low Dose Naltrexone is warranted. Especially because it has been proven to have qualitatively different effects at low doses than at high doses. They point out, by way of contextualizing that, that at doses 1/10 that of an analgesic dose, morphine has been shown to cause hyperalgesia.


    Here's one of the disclaimers:
    "An alternate explanation of LDN mechanism
    While we believe much data is consistent with that claim that LDN works via novel anti-inflammatory channels, there are alternative compelling explanatory models of the LDN mechanism. The most prevalent hypothesis, advanced by Dr. Ian Zagon and colleagues, states that inducing a small and transient opioid blockade will prompt the body to compensate by upregulating both endogenous opioids and opioid receptors [40]. The opioid upregulation effect of temporary naltrexone or naloxone blockade has been demonstrated multiple times previously [41, 42]. This “opioid rebound” effect could have multiple impacts on health and quality of life, including enhanced endogenous analgesia and repression of critical immune factors [40].

    Further research is needed with naltrexone and naloxone stereoisomers to determine the true mechanism of clinical action. In the meantime, we note that both the TLR4 and opioid receptor mechanisms may play a role in LDN action, as the hypotheses are not mutually exclusive."


    But like they note at the end of the disclaimer, por que no los dos? I personally have had euphoria from certain doses of low dose naltrexone. I was not going for that effect and it was too much and coincided with a dose that sort of "stimmed me out". But in my mind there's almost no doubt, simply from bioassay, that LDN causes some compensatory upregulation in opioid receptors. the question is whether that's what causes the therapeutic effect, and whether it can be tested more to find more specific markers for decreased inflammation.


    I highly recommend reading the full text.
     
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  6. debored13

    debored13 Senior Member

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    http://science.sciencemag.org/content/221/4611/671
     
  7. debored13

    debored13 Senior Member

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    Abstract
    Naltrexone, an opiate antagonist, had both stimulatory and inhibitory effects, depending on the dosage, on the growth of S20Y neuroblastoma in A/Jax mice. Daily injections of 0.1 milligram of naltrexone per kilogram of body weight, which blocked morphine-induced analgesia for 4 to 6 hours per day, resulted in a 33 percent tumor incidence, a 98 percent delay in the time before tumor appearance, and a 36 percent increase in survival time. Neuroblastoma-inoculated mice receiving 10 milligrams of naltrexone per kilogram, which blocked morphine-induced analgesia for 24 hours per day, had a 100 percent tumor incidence, a 27 percent reduction in the time before tumor appearance, and a 19 percent decrease in survival time. Inoculation of neuroblastoma cells in control subjects resulted in 100 percent tumor incidence within 29 days. These results show that naltrexone can modulate tumor response and suggest a role for the endorphin-opiate receptor system in neuro-oncogenic events.
     
  8. dreampop

    dreampop Senior Member

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    Great write-up and more insight into your theories. Do you have a background in biology? It's impressive that your able to keep all of this together - that executive functioning is perhaps my worst symptom after fatigue.

    I love that you brought that Light paper into it. I would have loved for Light to be part of a Center of Excellence, he produces really insightful studies. He did emphasize at the symposium that he didn't think fatigue was the proton/eatp/acid from normal fatigue but more like mitochondrial fatigue or immune fatigue, but he also said he found mitochondrial mutations that no one else has consistently found. I would be shocked (and more than a little scared) if that turned out to be true. We need to start naming these fatigues to differentiate them.

    His work also suggests ASIC3 receptor is upregulated in CFS after exercise (he also found il-10 high there, which must've been why I thought it was elevated in CFS). There is also a paper from Ronald Straud from the University of Florida, I don't know if you saw it, sorry if you did, that builds on Light's hypothesis by trapping metabolites in the arm's of PWCFS, thereby forcing them to interact with the receptors more. Fatigue and pain did increase I think. He also did a follow up paper where he blocked the receptors with lidiocaine, and this to some extent, blocked the fatigue. I don't know exactly, I read them a long time ago and am too brain dead to try right now.

    Anyway, great work, and take time to rest & recover.
     
    Last edited: Nov 15, 2017
  9. Murph

    Murph :)

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    Speaking of muscles and purines, this genetic disorder is surprisingly common and sure seems interesting:

    https://en.wikipedia.org/wiki/Adenosine_monophosphate_deaminase_deficiency_type_1

    --

    Adenosine monophosphate deaminase deficiency type 1, also called myoadenylate deaminase deficiency (MADD), is a recessive genetic metabolic disorder that affects approximately 1–2% of populations of European descent.

    Symptoms
    Although many people with a defective AMPD gene are asymptomatic, others may have symptoms such as exercise intolerance, muscle pain, and muscle cramping.

    EFFECTS


    Failure to deaminate the AMP molecules has three major effects. First, significant amounts of AMP are lost from the cell and the body. Second, ammonia is not freed when the cell does work. Third, the level of IMP in the cell is not maintained.

    • The first effect—the loss of AMP—is mostly significant because AMP contains ribose, a sugar molecule that is also used to make DNA, RNA, and some enzymes. Though the body can manufacture some ribose and obtain more from RNA-rich sources such as beans and red meat, this loss of ribose due to MADD is sometimes sufficient to create a shortage in the body, resulting in symptoms of severe fatigue and muscle pain. This outcome is especially likely if the individual regularly exercises vigorously or works physically over a period of weeks or months.
    • The second effect, the absence of ammonia, is not well understood. It may result in a reduction of the amount of fumarate available to the citric acid cycle, and it may result in lower levels of nitric oxide (a vasodilator) in the body, reducing blood flow and oxygenintake during vigorous exercise, though this may be offset by increased levels of adenosine, another vasodilator.[11]
    • The third effect, the reduction in IMP, is also not well understood. It may somehow result in a reduction in the amount of lactic acidproduced by the muscles, though serum lactate is typically slightly elevated with MADD

    --

    I am surprised we don't hear more talk of this as an exclusionary diagnosis.
     
    Last edited: Nov 17, 2017
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  10. debored13

    debored13 Senior Member

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    This is great work man
     
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  11. debored13

    debored13 Senior Member

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    I'm excited about this thread. I had to lower my LDN dose and am very tired, and also sleep deprived from too high of an LDN dose so I can't absorb much at the moment. but will return to it. excited to see how LDN fits into this theory
     
  12. debored13

    debored13 Senior Member

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    One thing I'm wondering if this theory covers is why some people get better simply from rest
     
  13. voner

    voner Senior Member

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    I am homozygous for this deficiency. @Valentijn maintains a database of 23andme data from ME/CFS patients and when I submitted my data to her she told me that out of 50 patients that she had in her database, I was the only person that was homozygous for AMPD1 deficiency.
     
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  14. debored13

    debored13 Senior Member

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  15. debored13

    debored13 Senior Member

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  16. debored13

    debored13 Senior Member

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    how did i miss that xanthines are purines... does this mean that caffeine could have an effect on cfs? or theobromine
     
  17. dreampop

    dreampop Senior Member

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    Some thoughts:

    About proton/eatp/la fatigue; I wonder if enough activation through different parts of the body, or through the body as whole elicits central fatigue (as opposed to just localized fatigue).

    I can't believe Straud bends over backwards to call it "central sensitization". Ugh. 1) His study isn't suggestive of central sensitization. 2) It's the peripheral nervous system when the nervous system is involved. 3) Probably most of the metabo receptors aren't even next to neurons.

    Could CD-39 autoantibodies (going for endothelial cells) mess with the blood brain barrier? The recent GWI/CFS mRNA study, one of the abnormal ones in CFS regulated the BBB.

    We have cerebral hypoperfusion in the midbrain, and the Japanese PET study showed microglia activation is overlayed on exact same area. Any ideas on what the heck is going on there.
     
    Last edited: Nov 20, 2017 at 11:14 PM
  18. dreampop

    dreampop Senior Member

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    Not, really, they antagonize adenosine receptors, which are downstream of the problem OP is suggesting. I tolerate caffeine fine, though many don't.
     
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  19. anni66

    anni66 mum to ME daughter

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    Many thanks @necessary8 for all your hard work. You have a gift for making " scientific speak" intelligible, and for those of us who struggle with papers, this is priceless.
     
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  20. junkcrap50

    junkcrap50 Senior Member

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    Of course, many thanks for this interesting, well thought, and well researched theory. That was a lot of work to do and many here appreciate your efforts.

    Are you or will you be able to theorize about any possible autoimmune drugs that may target specific mechanics of your theory in an attempt to lessen symptoms and offer some improvement (but not cure)? I'm sure there are some autoimmune or rheumatology drugs out that may help with your theory.
     

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