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Salvinorin a and allosteric modulation

Okay, on receptor proteins there are what's called the 'active site'- this is where the endogenous ligands bind. Agonists will bind at this active site as well.

An allosteric modulator will interact with some other site, either increasing or decreasing the activity of the endogenous ligand or an exogenous one.

Benzodiazepines, for instance, are positive allosteric modulators of GABA currents. In effect, they potentiate the effect of GABA at the active site.

I can't find a ref, but I believe this is what makes barbiturates so dangerous in combination with other drugs. I believe that Allosteric modulators + a direct agonist (especially those who activate the receptor more than the endogenous ligand) are so dangerous because instead of 1+1=2, the allosteric modulator potentiates that agonist at the receptor site, so 1+1 suddenly equals 6.
 
I quit smoking salvia, because it became dull when on opiates... I didn't find any difference to opiate effects, but salvia was boring on opiates...

serotonergic psychedelics work fine on opiates.



Just a side-note, nothing really constructive, I know ;)
 
Ham-milton said:
I can't find a ref, but I believe this is what makes barbiturates so dangerous in combination with other drugs. I believe that Allosteric modulators + a direct agonist (especially those who activate the receptor more than the endogenous ligand) are so dangerous because instead of 1+1=2, the allosteric modulator potentiates that agonist at the receptor site, so 1+1 suddenly equals 6.
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Yep, that sounds very good to me. "Synergistic effects" are more than just the sum of its several parts (i.e. 1+1=6).

The ref that you posted says:
Our first published studies indicated that Salvinorin A weakly inhibited mu-receptor binding, and subsequent experiments revealed that Salvinorin A partially inhibited mu-receptor binding. Therefore, we hypothesized that Salvinorin A allosterically modulates mu-receptor binding.
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Their hypothesis was confirmed. Salvinorin A is mu-receptor allosteric inhibitor. All effects mediated from this receptors are decreased in intensity. That would be? Analgesia, hypothermia, europhia (!), just to mention the most important ones. That explains to me to a certain extend the feeled effects of smoked Salvia.

Murphy
 
Canis aureus said:
I didn't find any difference to opiate effects, but salvia was boring on opiates
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If I understand correctly, the allosteric modulation of the MOR caused by the salvia will decrease (by inhibition) the binding capacities of these receptors...it's kinda opposite to what canis aureus felt but they said "weakly".

Anyway, salvia will not decrease tolerance by decreasing the binding of these receptors but should decrease the effect usually got from µ agonist.

thanks for the explanations :)
 
So really when people smoke Salvia they are feeling some of the symptoms of opiate withdawls. By being an mu-receptor allosteric inhibitor it makes less natural endorphans available kind of like the environment that happens when someone is withdawling from opiates. This does explain the extreame hot flashes, dysphoria, and general feeling of shit I feel after smoking Salvia.
 
So really when people smoke Salvia they are feeling some of the symptoms of opiate withdawls. By being an mu-receptor allosteric inhibitor it makes less natural endorphans available kind of like the environment that happens when someone is withdawling from opiates. This does explain the extreame hot flashes, dysphoria, and general feeling of shit I feel after smoking Salvia.
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No, that's not what it means at all. Salvia is a negative allosteric modulator. It decreases the effect of endorphins.

You are not feeling the effects of opiate withdrawals even slightly.

Besides being an allosteric modulator, it's also a Kappa agonist. That effect can explain all the other negatives.
 
lysergication said:
If I understand correctly, the allosteric modulation of the MOR caused by the salvia will decrease (by inhibition) the binding capacities of these receptors...it's kinda opposite to what canis aureus felt but they said "weakly".

Anyway, salvia will not decrease tolerance by decreasing the binding of these receptors but should decrease the effect usually got from µ agonist.
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Correct IMO; especially the underlined part is important: mu-antagonism should be experienced only very slightly if at all.
 
there's no antagonism at all. There will just be a decrease in effectiveness.
 
My understanding was that kappa agonists do not directly cause mu antagonism, but they do reduce the efficacy of mu-agonists, and in doing can give the subjective appearance of mu antagonism. For opioids that are agonist-antagonists and kappa agonists (like certain morphinans/benzomorphans), a better mu to kappa binding ratio (mu being proportionately higher) will generally indicate that the drug has a greater efficacy, or more specifically less side-effects (kappa agonists are analgesics, but the psychotomimetic properties are less to be desired when in severe pain, and may make the pain appear worse). Of course, a number of these drugs are sigma agonists as well, which may complicate this simplification...
 
This isn't about kappa agonists per se. The negative allosteric modulation that we're talking about is not the result of kappa agonism, but rather a kappa agonist that happens to be able to allosteric modulation of the mu receptor. Kappa agonism itself has no impact on this as far as I can tell. Kappa agonists are analgesics, but I don't think the psychotomimetic properties have ever been shown to increase pain- severe, moderate or mild. For a conscious, mobile patient, however, drugs like pentazocine, aren't the greatest drugs for the treatment of pain. They represent too great of risk of self-injury (accidental or otherwise) and depression.

I don't believe that sigma agonists lacking noncompetitive NMDA antagonism are not likely to produce major complicating effects.

The only sigma agonist I have much knowlege about hydrastine derivatives, which generally produce a drunken state that is somewhat similar to dextromethorphan, but much less intoxicating.
 
Ham-milton said:
there's no antagonism at all. There will just be a decrease in effectiveness.
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...this I wanted to say. Sorry for choosing the wrong words. Negro put it better:
negrogesic said:
...reduce the efficacy of mu-agonists, and in doing can give the subjective appearance of mu antagonism
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Of course one must not confuse agonist with antagonist. I meant more the apparent effect that is observed, i.e. decrease of mu-agonists effects.
 
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