Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation

Mechanism of μ-Opioid Receptor-Magnesium Interaction and Positive Allosteric Modulation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036724/

Magnesium is required for Mu-opioid receptors to function at all, and as such is essential to resolving the opioid crisis. All addiction recovery efforts MUST include multiform magnesium saturation.

Found this one two years ago purely by chance reading over “magnesium chloride” or “magnesium opioid” on Pubmed.

This is a truly amazing scalar over-the-top SHIFT in ALL Opiate ADDICTION TREATMENT GLOBALLY.

But also validates Magnesium Chloride as the most significant form of Magnesium to ensure consumption of BECAUSE…

When you put 99.99% Magnesium Chloride into any water, it will separate to form Mg2+ cations and Chloride cations floating free form fully dissolved!

I just don’t really understand how the entire brain nerd nootropic community has fallen for the false media dismissing Magnesium Chloride and going with patented Magnesium L-threonate at an unfortunate price. I can only chalk it up to complete refusal to take on first-hand experimentation to understand why so many use it everyday.

Print copies of this paper to hand out to anyone you may know who is struggling with addiction and/or acute or chronic pain.

It is also astonishing this came out of Mount Sinai hospital in NEW YORK, meaning CDC and FDA won’t be able to dispute it as foreign nonsense.

The contents of this paper are literally enough to justify legislating the change of addiction treatment protocols by the federal government to require Magnesium Ion Treatment as a success in addiction prevention in the first place, addiction recovery, and acute/chronic pain management.

A few key sentences…

“To reduce opioid doses, and thereby prevent or treat overdose and opioid use disorders, attention has recently shifted to the use of co-analgesics. Understanding how opioid receptor targets can be allosterically modulated by these elements, including cations, is key to the development of improved therapeutics. Here, we provide an atomic-level understanding of the mechanism by which magnesium binds to the μ-opioid receptor and enhances opioid drug efficacy by stabilizing the receptor activated state.”

“While the monovalent Na+ cation can decrease agonist affinity at the MOP Receptor (8), most likely through stabilization of the inactive conformational state of the receptor (e.g., see (9, 10)), the divalent Mg 2+ cation has the opposite effect (e.g., see (11)), suggesting it stabilizes an active-like conformation of the receptor.”

THIS ONE IS REALLY SIGNIFICANT AND IMPORTANT:

“A recent interdisciplinary study combining the results of 19 F-NMR and MD simulations on another prototypic GPCR, the adenosine A2A receptor (18), provided further support to the negative allosteric modulation of receptors by Na+ and their positive allosteric modulation by Ca2+ and Mg2+ . Not only did this work allow quantification of the effects of these cations on the conformational ensemble of the adenosine A2A receptor, but it also suggested important molecular determinants involved in the allosteric activation of this receptor in the presence of physiological cations.”

That is EXTREMELY significant because it means that this works on pretty much all receptor types for all cell types across the entire human body!

“Notable results of these studies were the unexpected finding that Na+ also stabilized an intermediate state that had previously been associated with partial agonism, while Mg2+ cations drove G protein-binding cleft opening, and consequent receptor activation, upon bridging specific acidic residues on the extracellular region of transmembrane helices 5 and 6 (TM5 and TM6) of the receptor (18).”

There is basically new knowledge of the intermediate state via Na+ (sodium ion), but they also verified the atomic physics of G-Protein Binding Cleft opening, activation, and thus enabling little tiny cellular nano tool control of opening and closing the Cleft via G-Protein with Mg2+ and Na+. Partial agonism of mu-opioid receptors via Na+/sodium ion means that the sodium ion can displace or kick off an opiate/opioid or endorphin/enkephalin (endogenous endorphins) from its binding site, Mg2+ (magnesium ion) does totally opposite to this in which case it activates and potentiates it.

Okay, those are the reasons this paper cannot be ignored across ALL OF MEDICINE, ALL OF MENTAL HEALTH, and ALL OF SURGICAL MEDICINE, etc. etc. etc. …

So the rest of the paper demonstrates the physics without any room to argue it’s accuracy and relevant and mandatory need for successful addiction/pain treatments significantly reducing doses of consumed opiates/opioids, preventing addiction to medications/drugs of ALL kinds, and the very definition of an Effective Drug Therapy of every kind!

And make sure you share it as far and wide as possible. PLEASE.

This is THE cornerstone guiding medicine. Everyone needs to print it and hand out copies to as many of the right places as possible.