Opioids Why does methadone not disinhibit dopamine release in the accumbens, as a mu receptor agonist, unlike other mu agonists?

[LikeADaVinci]

So, if you look at the bseline DA efflux in the nucleus accumbens and then compare the DA (dopamine) levels after peak plasma of methadone is achieved, you will notice an actual DECREASE in synaptic DA by about 10% …

Now, the orthodox school of thought as relating to activation of the mu receptor is that, there is a downstream inhibition of GABA inter neurons in the ventral tagmental area, thereby disinhibiting the release of dopamine to the NAC shell — this is thought to be inherent to activation of the mu receptor itself

Yet, methadone causes a net 10% DECREASE in DA in the NAC shell, and fentanyl causes only a 250% increase in DA efflux in the NAC shell, whereas traditional morphinon opioids such as heroin cause a 350% increase in DA efflux at the NAC shell at peak.

What gives?


Obviously the mu receptor is more complicated than we think, with simple agonist / antagonist / partial agonist activity … i postulate that the mu receptor has several (at least three) isoforms whereby the molecular docking in inherent to the: A) analgesic effects B) Respiratory Effects C) gastrointestinal effects D) effect on VTA GABA inter neurons which disinhibit Dopamine release to the NAC.

I think that the shape of the molecule is what causes activation of the different isoforms of the receptor to cause either of the four (or more?) functions to occur …

The reason I am wondering this, is that the analgesic activity seems to be inherently interrelated to addiction potential, rather than the downstream inhibition of GABA and increase in NAC dopamine levels, and so: maybe it is possible to model, chemically, the “missing” part of the methadone molecule as compared to morphine, to elucidate a compound which ONLY disinhibits dopamine without affecting the mu receptor isoform inherent to analgesic activity and hence: derive a molecule which causes the pleasure of inhibiting GABA in the ventral tagmental area, while not being so severely addictive (esp. physically addictive) as all (currently known) mu-receptor agonists are

P.S. interestingly, I have read in the literature that with traditional morphinons, a phenethyl substitution at the tertiary amine in E-ring (replacing n-methyl) produces a compound with DRASTICALLY LOWER addiction potential, while conferring 8-14 fold increases in potency,

And

14-methoxy moities added to traditional morphinons create a molecule which virtually lacks all respiratory depression! (While as well conferring a 500 fold increase in potency and 100 fold tighter binding affinity to the mu receptor)

I can dig up the references for the above claims if you need to see them

— there is a lot yet to be discovered about the Mu receptor, it seems !!! —

LikeADaVinci

 

[dneusingyrsago]

So, if you look at the bseline DA efflux in the nucleus accumbens and then compare the DA (dopamine) levels after peak plasma of methadone is achieved, you will notice an actual DECREASE in synaptic DA by about 10% …

Now, the orthodox school of thought as relating to activation of the mu receptor is that, there is a downstream inhibition of GABA inter neurons in the ventral tagmental area, thereby disinhibiting the release of dopamine to the NAC shell — this is thought to be inherent to activation of the mu receptor itself

Yet, methadone causes a net 10% DECREASE in DA in the NAC shell, and fentanyl causes only a 250% increase in DA efflux in the NAC shell, whereas traditional morphinon opioids such as heroin cause a 350% increase in DA efflux at the NAC shell at peak.

What gives?


Obviously the mu receptor is more complicated than we think, with simple agonist / antagonist / partial agonist activity … i postulate that the mu receptor has several (at least three) isoforms whereby the molecular docking in inherent to the: A) analgesic effects B) Respiratory Effects C) gastrointestinal effects D) effect on VTA GABA inter neurons which disinhibit Dopamine release to the NAC.

I think that the shape of the molecule is what causes activation of the different isoforms of the receptor to cause either of the four (or more?) functions to occur …

The reason I am wondering this, is that the analgesic activity seems to be inherently interrelated to addiction potential, rather than the downstream inhibition of GABA and increase in NAC dopamine levels, and so: maybe it is possible to model, chemically, the “missing” part of the methadone molecule as compared to morphine, to elucidate a compound which ONLY disinhibits dopamine without affecting the mu receptor isoform inherent to analgesic activity and hence: derive a molecule which causes the pleasure of inhibiting GABA in the ventral tagmental area, while not being so severely addictive (esp. physically addictive) as all (currently known) mu-receptor agonists are

P.S. interestingly, I have read in the literature that with traditional morphinons, a phenethyl substitution at the tertiary amine in E-ring (replacing n-methyl) produces a compound with DRASTICALLY LOWER addiction potential, while conferring 8-14 fold increases in potency,

And

14-methoxy moities added to traditional morphinons create a molecule which virtually lacks all respiratory depression! (While as well conferring a 500 fold increase in potency and 100 fold tighter binding affinity to the mu receptor)

I can dig up the references for the above claims if you need to see them

— there is a lot yet to be discovered about the Mu receptor, it seems !!! —

LikeADaVinci

methadone is a racemic mixture (two enantiomers left and right) in effect two drugs each has a distinct action on opiate receptors

 

[AlsoTapered]

Isomerism has nothing to do with it. the extremely slow onset of oral methadone that means it doesn't produce the dopamine mediated euphoria.

Anyone who has IV'ed methadone (and the UK did trial wet amps to hops) will tell you that YES, it's euphoric.

For what it's worth a few people figured out how to base out the methadone from the oral linctus and those people smoked (vaped) the result and it was in vogue for a while until people figured it didn't last for 24 hours and to maintain the euphoria one had to increase the dose.

The above did not end well.

 

[dneusingyrsago]

Isomerism has nothing to do with it. the extremely slow onset of oral methadone that means it doesn't produce the dopamine mediated euphoria.

Anyone who has IV'ed methadone (and the UK did trial wet amps to hops) will tell you that YES, it's euphoric.

For what it's worth a few people figured out how to base out the methadone from the oral linctus and those people smoked (vaped) the result and it was in vogue for a while until people figured it didn't last for 24 hours and to maintain the euphoria one had to increase the dose.

The above did not end well.

did amps for years in large doses (around 150mg usually 3 50mg amps) without alcohol and benzos sometimes a little morphine added cant say amps alone ever gave me euphoria apart from the not being sick pleasure you get after the chase ..canary wharf private doc to shirleys chemist then home to shoot up ...(i dont miss that lost many years to that journy)

 

[AlsoTapered]

Well you make a good point - YMMV due to tolerance.

But vaping the freebase... that was something else. I do not say this as in 'go for it' because people did and it never worked out for them.

But the low MP and high LogP of freebase methadone means the flash is rather impressive.