Receptor antagonists: Upregeulation or Downregulation?

[Poodles!]

I've been (mostly) lurking these forums for some years now and have learnt a surprising amount about pharmacology, neuroscience, biochemistry etc. One key point I've struggled to work is the effect of antagonists on different receptors. I should note that My drug journey began in 2007 with MDMA after excessive reading about it's pharmacology online. I only started reading about it because a bunch of my mates started doing it and I wanted to prove to them that drugs were bad and they should stop taking it!

Anyway, I've long believed that antagonists at monoamine receptors caused downregulation just as an agonists would. I assumed that it was the act of binding to a receptor, rather than activating it that caused the desensitisation, therefore higher binding affinity = stronger downregulation. Over the yearrs I've experimented with lots of different kinds oof drugs and tried to learn as much as I could about everything I put into my body. I've since seen what seems like conflicting information on receptor antagonists. For example, I've seen numerous studies stating that naloxone upregulates μ-opiod receptors.

So how do different receptors react to antagonists? And what is the mechanism behind downregulation or upregulation of these different receptors?

Thanks guys, and sorry if I'm missing something totally obvious!

 

[basement_shaman]

I think it varies from compound to compound and receptor to receptor, and I doubt there is a general rule.

 

[airsh0w]

You just have an oversimplified understanding of receptors. When an "agonist" or and an "antagonist" activates the receptor. There are many things it could activate or not activate. So two agonists for the same receptor could have different effects like psychedelics at 5-HT2A. This is called functional selectivity. So you can imagine how a partial agonist would activate one identical element of a receptor instead of two of them like a full agonist or something to that aspect. So it depends on if the components that are actionable are the same or different.

And that is just the beginning. Recently heteromeric receptors are being discovered which are combinations of known receptors but may have entirely different functions. There are listed as D1-D2 and CB1-A2A-D2.

Bottom line: It depends on what kind of antagonist it is. If it isn't activating anything then it is going to cause up-regulation.

 

[i are spectre]

in general and in reference to neurotransmitters and hormones:

smaller amounts of a substance will cause up-regulation and larger amounts of a substance will cause down-regulation, regardless if they are agonistic or antagonistic.

 

[Vaya]

For example, I've seen numerous studies stating that naloxone upregulates μ-opiod receptors.

I think this is due to a negative feedback loop; assuming naloxone binds to autoreceptors, a negative feedback loop would indicate that its antagonistic effects on the receptor would produce upregulation of the μ-opiod receptors. The same thing happens with potent DA agonists which bind to presynaptic DA neuron autoreceptors and, via negative feedback, tend to downregulate post-synaptic DA receptors.

It's just a theory, I'll have to look at naloxone's specific pharmacological profile to provide something more definitive....

~ vaya

 

[ProducedRaw]

in general and in reference to neurotransmitters and hormones:

smaller amounts of a substance will cause up-regulation and larger amounts of a substance will cause down-regulation, regardless if they are agonistic or antagonistic.

Could you please provide some references for this assertion?

 

[i are spectre]

Principles of Anatomy and Physiology, 13th Edition, Tortora/Derrickson, Chapter 18