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.
Highlights
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe systemic, acquired condition of unknown cause characterized by persistent or recurrent incapacitating fatigue accompanied by a range of multi-system manifestations [1]
Our results indicate that Naltrexone hydrochloride (NTX) restores TRPM member 3 (TRPM3)-like ionic currents in IL-2 stimulated natural killer (NK) cells from ME/CFS patients following 24 h incubation
Our findings indicate that NTX does not affect TRPM3-dependent Ca2+ signals when directly applied on both IL-2 stimulated NK cells from non-fatigued controls and ME/CFS patients, suggesting that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating mechanism
Summary
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a severe systemic, acquired condition of unknown cause characterized by persistent or recurrent incapacitating fatigue accompanied by a range of multi-system manifestations [1]. The etiology of ME/CFS remains elusive, immune dysfunction and abnormalities in natural killer (NK) cell functions are the most consistent laboratory immunological features [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. While there is an inconsistency in some immunological reports, differences in NK cell phenotypes and significantly reduced peripheral NK cell numbers resulting in significant reduction in NK cell cytotoxicity, have been reported in ME/CFS and implicated in disease severity [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
