Thank you for tuning me into this line of work - still so much to learn! Just based on a cursory glance my first thought is that I would love to see this study replicated with (+)-naltrexone, as (-)-naltrexone does still act on TLR4 in addition to MORs. They do some controls here to show NTX is acting as an antagonist versus a partial agonist, but if NK cells are the major target here I would imagine peripherally restricted MOR antagonists like methyl-NTX, which can't cross the blood-brain barrier, would be equally effective. Also would be a compelling reason to try different ratios of (+)-NTX to (-)-NTX to see whether there's an optimal trade off between the two!
Thanks again Janna!
One thought I also have on LDN concerns the TRPM3-channel that seems to regulate Ca2+-influx into Natural Killer cells.
They seem dysregulated/overstimulated.
(+)-LDN seems to reverse this dysregulation in vitro in ME/CFS and LC pts.
https://pubmed.ncbi.nlm.nih.gov/31736966/
https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00528-y
So mu-R antagonism seems needed in these instances.
Any thoughts on this?
Thank you for tuning me into this line of work - still so much to learn! Just based on a cursory glance my first thought is that I would love to see this study replicated with (+)-naltrexone, as (-)-naltrexone does still act on TLR4 in addition to MORs. They do some controls here to show NTX is acting as an antagonist versus a partial agonist, but if NK cells are the major target here I would imagine peripherally restricted MOR antagonists like methyl-NTX, which can't cross the blood-brain barrier, would be equally effective. Also would be a compelling reason to try different ratios of (+)-NTX to (-)-NTX to see whether there's an optimal trade off between the two!
Thnx for your reply. O yeah they probably used (-)-NTX.
It most certainly would be interesting to see if (+)-NTX would yield similar peripheral results in NK cells. Doubt it as they dont antagonize MORs.
Clinically I would prefer to hedge our bets for now, as antagonizing MORs seems implicated in indirectly activating those TRP-channels in NK-cells.
If methyl-NTX does not cross the BBB or blood-spinal-barrier it wouldn't matter if they inhibit TLR4 in microglia, right?
How do I convince my physician to prescribe it??