Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From ME/CFS patients

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Front Immunol. 2019 Oct 31;10:2545. doi: 10.3389/fimmu.2019.02545. eCollection 2019.
Naltrexone Restores Impaired Transient Receptor Potential Melastatin 3 Ion Channel Function in Natural Killer Cells From Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.
Cabanas H1,2,3, Muraki K3,4, Staines D1,2,3, Marshall-Gradisnik S1,2,3.
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Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a seriously long-term and debilitating illness of unknown cause hallmarked by chronic pain and fatigue, memory and concentration impairment, and inflammation. ME/CFS hypothesis involves impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signaling and Natural killer (NK) cell functions.

Currently, substances called opioids, agonists of mu (μ)-opioid receptors (μOR), are the strongest painkillers clinically available for people suffering from strong or long-lasting pain characteristic of ME/CFS. μOR have been reported to specifically inhibit TRPM3 and to be expressed in immune cells where they play an immunomodulatory and immunosuppressive role. Naltrexone hydrochloride (NTX) acts as an antagonist to the μOR thus negating the inhibitory function of this opioid receptor on TRPM3.

Therefore, understanding the mechanism of action for NTX in regulating and modulating TRPM3 channel function in NK cells will provide important information for the development of effective therapeutic interventions for ME/CFS. Whole-cell patch-clamp technique was used to measure TRPM3 activity in Interleukin-2 (IL-2) stimulated and NTX-treated NK cells for 24 h on eight ME/CFS patients and 8 age- and sex-matched healthy controls, after modulation with a TRPM3-agonist, pregnenolone sulfate (PregS), NTX and a TRPM3-antagonist, ononetin.

We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in IL-2 stimulated NK cells after modulation with PregS and ononetin.

Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 h with NTX. Moreover, we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating.

The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.

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What's good here: More confirmation of their basic finding of TRPM3 inhibition, and a suggestion of how to restore it. It basically explains why low dose naltrexone works in some people.

What's bad here: The context. No other research groups are onto the TRPM3 angle. Ron Davis tried to replicate the most basic finding, of a problem with TRPM3 in me/cfs, and couldn't. These guys have gone a long way down this road, extending their basic finding in many ways. This makes them either lone visionaries or quite wrong.

I really want them to be lone visionaries, from a huge range of angles, including obviously getting a cure, but also just to see a low-status university in a crappy part of Australia upstage Harvard and Stanford! But I worry about whether that's going to happen.
 
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Marylib

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@Murph Does anyone know where the Stanford collaboration (Ron Davis and company) states they were unable to replicate the findings of the Australian group concerning the problem with the TRMP3 calcium ion channels in various organs of the body? I have read this in various comments on the forum, but I wasn't sure if Open Medicine Foundation had published anything on this. Obviously I missed something. Thanks.
 
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SlamDancin

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I’m trying high dose Naltrexone. I already had an idea that overactive opioid receptors were in play so I tried to see if I could achieve a different response using high dose (low dose didn’t do much for me). After a couple weeks of 25-50mg a day I do feel better and like I’m healing better from the PT I’m doing myself on my EDS-like condition. It also seems to have an anti-fatigue and anti-sickness behavior effect. At first it may be unpleasant as it’s anxiogenic due to released serotonin and possibly nitric oxide and cortisol. I tried to control those factors with inhibitors. There is an old study on CFS from Spain (who knows what diagnostic criteria they used it was 1989) though that Naloxone reversed several dysfunctional properties of pwME’s monocytes. Just my two cents.
 

SlamDancin

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Call me crazy but I look forward to taking my dose of 50 mg Naltrexone now, about two weeks in. Wikipedia says it’s been trialed for depersonalization because of it’s antagonism of kappa opioid (think salvia as an agonist at this receptor). I believe my depersonalization is a symptom of the illness and I think it really is helping that symptom which lowers anxiety and improves fatigue along with it. I don’t know guys there may be something to high dose Naltrexone.
 

Marylib

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I’m trying high dose Naltrexone. I already had an idea that overactive opioid receptors were in play so I tried to see if I could achieve a different response using high dose (low dose didn’t do much for me). After a couple weeks of 25-50mg a day I do feel better and like I’m healing better from the PT I’m doing myself on my EDS-like condition. It also seems to have an anti-fatigue and anti-sickness behavior effect. At first it may be unpleasant as it’s anxiogenic due to released serotonin and possibly nitric oxide and cortisol. I tried to control those factors with inhibitors. There is an old study on CFS from Spain (who knows what diagnostic criteria they used it was 1989) though that Naloxone reversed several dysfunctional properties of pwME’s monocytes. Just my two cents.
Thanks for your comment. It seems that most people jump to low-dose naltrexone, while the study is not specifying any dose. This is not a study of clinical cases, after all, but having a drug applied to a cell to determine if there is an immune response (NK cells) - at least this is my understandng @SlamDancin. When you say inhibitors to what happens with 50 mg naltrexone, what do you refer to? Do you mean the benzo's? Thanks.
 
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@Marylib I think I've tracked this claim back to its source.

First I found this old comment referring to something I saw in the comment section on Cort's blog.

Totally incidentally, Janet, citing Ron, also drops a rebuttal to the work done by the Aussie researchers on calcium. I had wondered whether anyone had tried to replicate their findings.

> Ron says: We do not find that those mutations that are reported from Griffiths come out as significant in our studies (see Wenzhong’s SIPs study slide on mutations from the symposium). Furthermore, those mutations appear to be common in the European population of healthy people.
Then I tracked down that YouTube video from the symposium and you can see OMF researcher Wenzhong Xiao put up a slide that says differences in TRPM3 were not significant in their severely ill patient study. (17 minute mark, I've tried to cue it up so that's where the video starts if you just click play.)

 

Marylib

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@Murph. Thanks very much for all the effort you put into finding this. I guess the Aussie's are sticking with their hypothesis in 2019. Let's just hope that someone has some answers in terms of treatment and it is good that so many scientists are working on it now.
 
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