Ultra low dose naloxone? Not naltraxone

[Cotcha Yankinov]

So naltrexone is not working primarily for tolerance by preferentially blocking MOR with altered G protein coupling, but rather just blocks the abnormal coupling due to interaction with Filamin A? Although I understand both effects could play a role.

May dextro-naltrexone possess this Filamin A affinity even though it does not possess significant opioid receptor affinity?

 

[serotonin2A]

So naltrexone is not working primarily for tolerance by preferentially blocking MOR with altered G protein coupling, but rather just blocks the abnormal coupling due to interaction with Filamin A? Although I understand both effects could play a role.

May dextro-naltrexone possess this Filamin A affinity even though it does not possess significant opioid receptor affinity?

It seems unlikely that ULD naloxone is acting on MOR-Gs because the occupation level reportedly does not exceed 1%.

 

[Cotcha Yankinov]

Do you think receptor occupation % may not be as important if an inverse agonist is causing the Gs coupled MOR to disappear? In other words, at any given time the receptor occupation does not exceed 1%, but maybe if it is causing downregulation of the MOR-Gs over time, the overall effect on MOR-Gs levels could be more significant? I understand this hinges on either the ligand having preference for the Gs coupled MOR, or maybe more than 50% of the MOR would have to be coupled to Gs...

I suppose another scenario is modulation of tolerance/withdrawal via effects on microglia.

 

[serotonin2A]

Do you think receptor occupation % may not be as important if an inverse agonist is causing the Gs coupled MOR to disappear? In other words, at any given time the receptor occupation does not exceed 1%, but maybe if it is causing downregulation of the MOR-Gs over time, the overall effect on MOR-Gs levels could be more significant? I understand this hinges on either the ligand having preference for the Gs coupled MOR, or maybe more than 50% of the MOR would have to be coupled to Gs...

I suppose another scenario is modulation of tolerance/withdrawal via effects on microglia.

There is a good readout for MOR inverse agonist activity in opioid dependent individuals -- precipitated withdrawal. If a dose of an inverse agonist isn't inducing precipitated withdrawal then that is a pretty good indication that it isn't doing much to MOR. Opioid dependent individuals are often sensitive to small reductions in opioid dose, so they should also be sensitive to low levels of naloxone/naltrexone binding to MOR.

 

[Cotcha Yankinov]

Opioid dependent individuals are often sensitive to small reductions in opioid dose, so they should also be sensitive to low levels of naloxone/naltrexone binding to MOR.

I hope I'm reading between the lines correctly here - if MOR-Gs coupling was significant AND MOR-Gs had enhanced ligand affinity, opioid dependent individuals should actually experience relief with a lowering of MOR agonist dosage due to less stimulation of MOR-Gs?

The only possible way to save the "ULDN blocks MOR-Gs" theory that I can think of is that after the (possible) MOR affinity change, affinity is enhanced more so for the inverse agonist ligands relative to MOR agonists, otherwise if affinity was unchanged and there was no Filamin A interaction, you might need more than 50% of the MOR to be coupled to Gs for ULDN to have a relieving effect. Or one MOR-Gi/o activation would have to be not enough to negate one MOR-Gs activation.

I think some of my confusion may stem from the alteration of affinities with ligands of MOR-Gs that seems necessary for the theory of ULDN functioning by preferentially blocking said MOR-Gs - was there evidence for an increase in affinity with MOR-Gs, or was this just proposed to fill in the gaps of the theory?

I see now the affinity of the MOR inverse agonists with Filamin A is 200 times higher than that of the inverse agonists for MOR, so I suppose the old theory isn't needed...


Also, is it possible that a ligand that has been characterized as an inverse agonist at MOR-Gi/o is not signaling through that same receptor homeostasis type cascade when binding to MOR-Gs?

 

[serotonin2A]

I hope I'm reading between the lines correctly here - if MOR-Gs coupling was significant AND MOR-Gs had enhanced ligand affinity, opioid dependent individuals should actually experience relief with a lowering of MOR agonist dosage due to less stimulation of MOR-Gs?

The only possible way to save the "ULDN blocks MOR-Gs" theory that I can think of is that after the (possible) MOR affinity change, affinity is enhanced more so for the inverse agonist ligands relative to MOR agonists, otherwise if affinity was unchanged and there was no Filamin A interaction, you might need more than 50% of the MOR to be coupled to Gs for ULDN to have a relieving effect. Or one MOR-Gi/o activation would have to be not enough to negate one MOR-Gs activation.

I think some of my confusion may stem from the alteration of affinities with ligands of MOR-Gs that seems necessary for the theory of ULDN functioning by preferentially blocking said MOR-Gs - was there evidence for an increase in affinity with MOR-Gs, or was this just proposed to fill in the gaps of the theory?

I see now the affinity of the MOR inverse agonists with Filamin A is 200 times higher than that of the inverse agonists for MOR, so I suppose the old theory isn't needed...

I think the idea that naloxone has higher affinity for MOR coupled to Gs vs. MOR coupled to Gi/o is a interpretation based on the results of functional studies -- I don't think the affinity was actually measured in binding studies.
Now that a high affinity naloxone binding site on filamin A has been identified, it looks like the earlier interpretation was probably wrong.

Also, is it possible that a ligand that has been characterized as an inverse agonist at MOR-Gi/o is not signaling through that same receptor homeostasis type cascade when binding to MOR-Gs?

Are you asking whether an inverse agonist at MOR-Gi would also have to be an inverse agonist of MOR-Gs? Efficacy measures are dependent on the coupling mechanism, so it is entirely possible that a ligand could act as an inverse agonist for one pathway and an agonist for another pathway.