Binding: some short vs long half life questions (for the experts)

[~_Hiss_~]

Let's say for instance, someone takes methadone, a full mu-agonist. But people don't get that rush kind of high you do with oxycodone, fentanyl or diamorphine, which all have short half lives. Why are short half life opiates better shit? Same with benzos... valium comes on slow and doesnt have much bang, but halcion is pretty euphoric. both opposite ends of the spectrum there, too.

I understand downregulation occurs with repeated binding, which ends up leading to dependence or changes, such as with opioids. So, when a drug binds, and an action potential is sent out (or inhibition of one), how long does the drug stay bound to the receptor? Does it continually stimulate it until its decayed with a time according to its half life? Does it unbind and go on to bind to other neurons? I've noticed tolerance can skyrocket after methadone doses; is it because the molecules stay bound to the same neurons for a long time, or do they stay a while, then unattach and still have plenty of time to affect other neurons?

Hope this isn't written too messy. Its been bugging me curiosity wise.

Peace,
Hiss

 

[MattPsy]

Full agonists bind and then dissociate almost immediately. Partial agonists stay bound for a short while.
As for the methadone and euphoriant properties, i'd take a guess at it being more to do with it's different mu:kappa:delta binding ratios - but I know little about opioid pharmacology unfortunately.
Oh, and also methadone has strong NMDA antagonism, I guess that would probably interfere with it's euphoric potential.

 

[Ham-milton]

Some partial agonists may stay bound for quite a while, AFAIK. buprenorphine, for instance.

I would imagine that having ligands binding, dissociating, binding to the receptor again and again, and signals being sent out at a high frequency would be more enjoyable than just every once in a while. And it is!

Though in my experience with cannabinoids, that doesn't hold true.

 

[MattPsy]

^ Cannabinoid receptors are expressed in a much higher density than other neurotransmitter sites, all throughout the body. That's why full agonist cannabinoids are 1) unpleasant and 2) possibly dangerous. You can't overdose on THC very easily... but HU210 you probably could.

 

[Ham-milton]

I can't find much about truly dangerous cannabinoid overdoses, mostly just ill-informed freak-outs. Any data available on real cannabinoid overdoses?

 

[LuxEtVeritas]

^ almost no one has ever had access to full agonists like HU-210 so you will not hear of such overdoses and as stated one can not really OD on partial agonists such as cannabis and any of its cannabinoids therein

also i have wanted to see effects of other full agonists, partciulrly endogenous such as Noladin/2-AG, in vivo but have not heard any research there either