Naltrexone restores impaired transient receptor potential melastatin 3 ion channel function in NK cells from ME/CFS patients, Cabanas et al, 2019

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 ion channel disorders and more specifically impaired Transient receptor potential melastatin 3 (TRPM3) ion channel function, affecting calcium signalling 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 CFS/ME. 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 hours on sixteen age- and sex-matched healthy controls and CFS/ME patients, after modulation with pregnenolone sulfate (PregS), NTX and ononetin.

We confirmed impaired TRPM3 function in ME/CFS patients through electrophysiological investigations in Interleukin-2 (IL-2) stimulated NK cells after modulation with pregnenolone sulfate and ononetin. Importantly, TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation for 24 hours 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 CFS/ME patients, resulting in calcium signals remodelling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for CFS/ME. 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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for people suffering from strong or long-lasting pain characteristic of CFS/ME
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Is it just me, or is that description more likely to be someone with FM rather than ME? I get muscle pain but it stops within seconds of stopping whatever I am doing. I don't get the kind of pain that would require pain meds, whereas my S-I-L has FM and requires heavy-duty pain meds.
 
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.

This would only make sense if we think that PWME actually have an immune defect relevant to their symptoms involving NK cells. There seems pretty little evidence for that. I am not sure there is much evidence for opiates being immunomodulatory or immunosuppressant. People who use heroin regularly but otherwise keep well with good nutrition do not have immunodeficiency as far as I know.
 
There doesn't seem to be any evidence of thermal hyperalgesia in ME (TRPM3 being highly expressed in the sensory system and associated with thermoreception). Also, the fenamate NSAIDs are TRPM* antagonists (mefenamic acid, widely available OTC, being one of the most TRPM3 selective) - wouldn't it be likely that we would have clinical evidence of any substantive association between the fenamates and ME symptoms by now?

I might just be brain-fogged, and I've only briefly skimmed the full paper, but I just can't see how impaired TRPM3 function alone can be associated with the core symptoms of ME.
 
Andy said:
Cohort of eight patients and eight controls. Given all the money they get I wonder when they'll start doing proper sized studies?
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dr Marshall-Gradisnik made it clear when they published their first study relating to their patch-clamp experiment that they didn’t need high sample size to prove their point.

This current paper certainly looks like a pilot study, to be followed by larger sample, and accompanied by bigger investments.
 
glimpsesofme said:
There doesn't seem to be any evidence of thermal hyperalgesia in ME (TRPM3 being highly expressed in the sensory system and associated with thermoreception). Also, the fenamate NSAIDs are TRPM* antagonists (mefenamic acid, widely available OTC, being one of the most TRPM3 selective) - wouldn't it be likely that we would have clinical evidence of any substantive association between the fenamates and ME symptoms by now?

I might just be brain-fogged, and I've only briefly skimmed the full paper, but I just can't see how impaired TRPM3 function alone can be associated with the core symptoms of ME.
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Isn't heat-intolerance a common symptom of me/cfs for many? Of course it has many causes.

I admit, although largely ignorant, I have always been interested in the TRPs because of the many strange intolerances pwme have - I think of a patient complainng a touch or vibration causes them distress. And of course, heat.
 
Milo said:
dr Marshall-Gradisnik made it clear when they published their first study relating to their patch-clamp experiment that they didn’t need high sample size to prove their point.

This current paper certainly looks like a pilot study, to be followed by larger sample, and accompanied by bigger investments.
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And I'm still unconvinced by their argument on how small sample sizes are acceptable in their work. The test they are using may be a gold standard, but without testing it on larger sample sizes we don't know that it is safe to generalise the results in the way that they do.
 
I’ve only skim read this so far, but I’m feeling sceptical. Their stated hypothesis is that the TRPM3 impairment is the underlying mechanism driving the condition. In this study, it sounds like they are saying that naltrexone fixes that impairment:
Importantly, we demonstrated that TRPM3 channel activity was restored in IL-2 stimulated NK cells isolated from ME/CFS patients after incubation with NTX for 24 hours.
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Functioning of the ion channel was “restored” not improved. Given that they claim that the TRPM3 channel impairment is the cause of all our symptoms, that sounds like they’re saying that the problem has gone away after naltrexone treatment. Essentially, presenting naltrexone as a cure. But anecdotal evidence suggests that it isn’t a cure. It seems to help some (I’m one of the lucky ones), but others it doesn’t help at all, and some it makes worse. I don’t know too many who would say that they experienced restored functioning with naltrexone.

I wonder how they would explain the mixed results from naltrexone given this claim that it restores TRPM3 function? If anything, doesn’t this undermine their hypothesis about TRPM3 being the underlying mechanism (because, based on the results of this study, those taking naltrexone would have their TRPM3 channel functioning restored and yet are probably still be symptomatic)?

Unless I’ve completely got the wrong end of the stick?
 
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God you'd swear they just discovered ldn and it was brand new... I've no faith in this gang. They are good at blowing their own trumpet I'll give them that. Ldn did not help me, I tried three times starting very low. I fainted at one stage and I've never fainted in my life. So it's certainly not a fix all. They've some brass neck. No wonder Ron Davis and team have steered clear.
 
InitialConditions said:
I hope these results won't be oversold
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Sorry, if the past is anything to go by then it is guaranteed that NCNED will oversell it.

NCNED Facebook post said:
Groundbreaking research from NCNED
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Groundbreaking huh?

NCNED is the peak research centre nationally and is internationally recognised for its world-leading research on the identification of the pathology, developing a screening test and pharmacotherapeutic intervention for ME/CFS.
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Peak research? World-leading? "identification of the pathology, developing a screening test and pharmacotherapeutic intervention for ME/CFS"??

NCNED researchers were the first in the world to develop the gold-standard in experimental research known as patch clamp technique in immune cells to measure TRP receptor function.
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In this new pivotal research publication
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Pivotal? Is it? It's been demonstrated on eight subjects - that isn't proof of it being pivotal for me.

This groundbreaking discovery
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Maybe, maybe not.

This world first discovery suggests - /.
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Their constant "worlds first, ever, bestest, bigly, discovery that will cure everything" hype taints any research results that they put out for me. Compare to Mike VanElzakker in my Q&A with him, who was at pains to point out that anything we discussed about his research was talking about initial, early results and shouldn't be taken as conclusive proof or evidence of anything. Or compare them to Fluge & Mella, who did their best to play down the hype around rituximab. I'd hate to think what it would have been like if NCNED had been in the same position as F&M - there probably would have been headlines around the world that they had discovered the cure.
 
Naltrexone is one of the few things that we can be 100% sure doesn't work for ME/CFS given how many clinicians prescribe it to our patient population in the States and how many of us have tried it on our own without any major benefit. It's so widely available and cheap compared to something like RTX which needed a huge trial to debunk it.
 
Sid said:
Naltrexone is one of the few things that we can be 100% sure doesn't work for ME/CFS given how many clinicians prescribe it to our patient population in the States and how many of us have tried it on our own without any major benefit. It's so widely available and cheap compared to something like RTX which needed a huge trial to debunk it.
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Naltrexone works fantastically for me. I went from being almost as sick as Whitney Dafoe to using my laptop several hours a day, listening to audiobooks, sitting in bright rooms, and holding prolonged conversations in a matter of weeks.
 
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