Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome: role of Transient Receptor Potential Melastatin 3 Ion channels in pathophysiology and treatment, by
Helene Cabanas,  Katsuhiko Muraki,  Natalie Eaton-Fitch,  Donald Ross Staines and Sonya Marshall-Gradisnik in Front. Immunol., 13 July 2021 [doi.org/10.3389/fimmu.2021.687806]


Research abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multi-systemic chronic condition of unknown aetiology classified as an immune dysfunction syndrome and neurological disorder.

The discovery of the widely expressed Transient Receptor Potential Melastatin 3 (TRPM3) as a nociceptor channel substantially targeted by certain opioid receptors, and its implication in calcium (Ca2+)-dependent Natural Killer (NK) cell immune functions has raised the possibility that TRPM3 may be pharmacologically targeted to treat characteristic symptoms of ME/CFS.

Naltrexone hydrochloride (NTX) acts as an antagonist to the mu (μ)-opioid receptor thus negating its inhibitory function on TRPM3. Based on the benefits reported by patients on their symptoms, low dose NTX (LDN, 3.0–5.0 mg/day) treatment seems to offer some potential benefit suggesting that its effect may be targeted towards the pathomechanism of ME/CFS.

As there is no literature confirming the efficacy of LDN for ME/CFS patients in vitro, this study investigates the potential therapeutic effect of LDN in ME/CFS patients. TRPM3 ion channel activity was measured after modulation with Pregnenolone sulfate (PregS) and ononetin in NK cells on 9 ME/CFS patients taking LDN and 9 age- and sex-matched healthy controls using whole-cell patch-clamp technique.

We report that ME/CFS patients taking LDN have restored TRPM3-like ionic currents in NK cells. Small ionic currents with a typical TRPM3-like outward rectification were measured after application of PregS, a TRPM3-agonist, in NK cells from patients taking LDN. Additionally, PregS-evoked ionic currents through TRPM3 were significantly modulated by ononetin, a TRPM3-antagonist, in NK cells from ME/CFS patients taking LDN.

These data support the hypothesis that LDN may have potential as a treatment for ME/CFS by characterising the underlying regulatory mechanisms of LDN treatment involving TRPM3 and opioid receptors in NK cells.

Finally, this study may serve for the repurpose of marketed drugs, as well as support the approval of prospective randomized clinical studies on the role and dose of NTX in treating ME/CFS patients.


Sydney Morning Herald: Common drug could be a simple solution to a complex disease

Griffith University researchers have identified in lab experiments that low doses of naltrexone reverse abnormal cell functions associated with chronic fatigue syndrome, which clinicians refer to as myalgic encephalomyelitis (ME).

Griffith University professor Sonya Marshall-Gradisnik said their finding that naltrexone could treat the disease came on top of previous research – also a world first – in which the team proved that a defect in a specific ion channel in certain cells in the body, called TRPM3, was the cause of ME.

“It’s the first time these channels have ever been found to be faulty [in ME patients], and we’ve reproduced that four separate times,” Professor Marshall-Gradisnik said.

Gritffith news: World-first laboratory study finds low-dose Naltrexone may improve ME/CFS symptoms

“This study serves to support the repurposing of marketed drugs and support prospective randomised clinical trials using Naltrexone in treating ME/CFS patients,’’ Prof Staines said.

The world-first scientific research study was achieved using the gold standard of Patch Clamp electrophysiology (PCE) which examines cellular ion currents in pathophysiology and potential pharmacotherapeutics in selected cells from ME/CFS patients and healthy control volunteers.

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