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Trifluoperazine and opioid tolerance reversal

Mr Blonde

Mr Blonde

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Good evening, fellow BL'ers. :D

First, this article should be read.

I have access to trifluoperazine, an old-school anti-psychotic that is now rarely used due to some of the nasty side-effects it can produce. I've used it several times, with little to no ill effect, and a purposeful overdose on the substance did not produce anything more then sever agitation and muscle soreness for several days. So I'm fairly confident about weathering effects from this drug itself.

I am considering doing an experiment on tolerance reversal with this substance; from what I've gathered, it may work by promoting up-regulation of receptors but I'm not sure. I do remember once reading an article that suggested it could prevent opioids from working, but I am no longer able to find this article.

Basically, I would like some advice and theorizing from other people on how exactly this substance may reverse tolerance and what I might expect if I try it out. My comprehension skills are not at their best right now, and I'm having trouble understanding some things. Could anyone explain to me what role calmodulin dependent protein kinase II has in opioid tolerance and in how trifluoperazine works? Is this the major way that this drug may reverse tolerance or may there be other mechanisms at play here?

I have been unable to find much information from trifluoperazine users on here, some users of other anti-psychotics have reported nice experiences with their drug and opioids. Can anyone think of a specific reason why trifluoperazine would produce this effect and not other anti-psychotics from the same family?

Long reading, hopefully someone gets through it. :)

Cheers,

Mr Blonde
 
I would be really careful with experiments involving phenothiazines. Some of the malign side-effects, namely akathisia and tardive dyskinesia, can occur years after the drug was applied.
I admit, this is more probable when taking these drugs in the long-term, but you should trade off the risks against the insight that such an experiment can bring with maximum care!!!

With regard to your question:
Mr Blonde said:
Could anyone explain to me what role calmodulin dependent protein kinase II has in opioid tolerance and in how trifluoperazine works?
Click to expand...
In short, as I understood it:
Ca2+/calmodulin dependent protein kinase II (CaMKII) is one part of the complex biochemical network of reactions that leads to development of tolerance to opioid analgesia. It does so by phosphorylating the µ-receptor, thus deactivating it. I think that 'deactivation' is not an absolute but a relative term in this case. The phosphorylation probably induces a change of the 3-dimensional conformation of the µ-receptor, so that ligands bind to it resp. activate it with less efficacy. A complete deactivation down to 0% activity is usually a rare event.
The activity of CaMKII is dependent of at least two co-factors: Calcium ions and calmodulin. Both factors are up-regulated by opioids, thus leading to an increased activity of CaMKII. This results finally in a prolonged desensitization of the µ-receptors.[1] As said above, this is just one of several mechanism that make up the phenomenon 'opioid-tolerance'.
Trifluoperazine is a potent antagonist of calmodulin [2], thus suppressing calmodulin and CaMKII activity. This is thought to be the responsible mechanism for the reversal of induced opioid tolerance.


References:
[1] "Effects of acute and chronic morphine treatment of calmodulin activity of rat brain", Mol Pharmacol 1982, 22, p.389; "Increase of calmodulin III gene expression by mu-opioid receptor stimulation in PC12 cells", Jpn J Pharmacol 2000, 84, p.412; "Differential effects of µ-opioid receptor ligands on Ca(2+) signaling", J Pharmacol Exp Ther 2002, 302, p.1002; "The effects of recombinant rat mu-opioid receptor activation in CHO cells on phospholipase C, [Ca2+]i and adenylyl cyclase", Br J Pharmacol 1997, 120, p.1165
[2] "Pharmacological antagonism of calmodulin", Can J Biochem Cell Biol 1983, 61, p.927


Cheers! - Murphy
 
^ If trifluoperazine is preventing CaMKII from doing it's thing, and according to Murphy's post CaMKII is affecting the mu receptor, why wouldn't it affect euphoria also?

MurphyClox: Thanks for the very informative post! I am well aware of the risks trifluoperazine carries, I was in fact very surprised to discover my friend is Rx'd it. I have heard some horror stories about it in one off doses, which is scary, but I am confident I do not have to worry about this after having used it multiple times. Still, I will be careful and start off with low doses of the drug first.

Hopefully this experiment yields some results... does anyone know a good way to field test for analgesic properties without causing myself undue harm?
 
The euphoria from opiates are not just due to the opiate receptors, also dopamine and serotonin. Anti-psychotics block some dopamine and serotonin receptors.

I'm sure it will shim some euphoria off, but increase the pain-killing effects.
Same as when taking an opiate with chlorpromazine, which is a similar chemical.

I would not be surprised to see this in combo with an opiate in some "Abuse Proof" pill. (Like we all haven't heard that before.)

Also, In the medical world, always note to yourself that euphoria is a "Side Effect."
So, I'm sure they are not even looking into that.
 
Last edited:
^ Ah OK, yes I understand now it was in front of me all along. :)

Yeah, I'm aware they view euphoria as a side effect, I doubt they were gonna look into it with mice though. ;)

I'm still going to test this out any how, possibly see how it affects analgesic properties as well. My curiosity will not be sated otherwise!
 
If I remember correctly NMDA antagonism has shown to reduce/reverse tolerance to opiates in an extent. I'd find if trifluoperazine has any NMDA antagonist properties.
 
NMDA antagonism also increases euphoria and respiratory depression.

If it does have NMDA antagonistic properties, won't some euphoria still be mitigated by blocking of dopamine and serotonin?
 
NMDA antagonists wouldn't seem to be a good property for a drug aimed to treat schizophrenia.

Murphy, thanks again for another informative post!
 
negrogesic said:
NMDA antagonists wouldn't seem to be a good property for a drug aimed to treat schizophrenia.

Murphy, thanks again for another informative post!
Click to expand...

Not if the NMDA drug has no dopamine or serotonin blocking properties.
If it does, then it might be a novel antidepressant with the mood lift NMDA antagonist give at sub-anesthetic doses.

Then again, it might be a miserable dud for opiate abusers cutting into the euphoria, and dulling an experience.
 
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