Irreversible mu-opioid agonists - good for subchronic severe pain?

[TSLexi]

Hey! I have an interesting question:

I once had a severe case of localized necrotizing stomatitis that caused such severe pain that 60 mg/day hydrocodone didn't even take the edge off. In fact, the only thing that would relieve the pain was a lidocaine nerve block, but my dentists told me I couldn't come back every two hours, so I just had to make do with a huge Norco script.

Don't worry, everything's great now.

I was wondering if an irreversible mu-opioid agonist, like oxymorphazone, would've been an effective analgesic, since it permanently activates the mu-opioid receptors.

Thanks!

 

[DelRi0]

I'm not so sure about that man... Irreversible doesn't necessarily mean that they just "stay activated" forever and you don't have to re dose. It's more of once it binds to the receptor site it doesn't unbind, even after the neurotransmitters stop flowing from it. It basically turns your receptors into "use once and dispose" receptors. Your body will eventually shut them down and disregard them along with maybe or maybe not making more to replace them so basically it's just a really nasty thing to even think about. You would risk losing receptor sites and with the less you have, the harder it is for agonists to bind and work right.

 

[TSLexi]

I'm not so sure about that man... Irreversible doesn't necessarily mean that they just "stay activated" forever and you don't have to re dose. It's more of once it binds to the receptor site it doesn't unbind, even after the neurotransmitters stop flowing from it. It basically turns your receptors into "use once and dispose" receptors. Your body will eventually shut them down and disregard them along with maybe or maybe not making more to replace them so basically it's just a really nasty thing to even think about. You would risk losing receptor sites and with the less you have, the harder it is for agonists to bind and work right.

I know that irreversible means stays bound until the receptors get recycled. I studied pharmacology at university in one of my courses. It means you have to redose less often, because you won't lose the drug before the receptors get recycled.

 

[DelRi0]

Well, yeah, that's kinda what I was trying to get at. I thought you were under the impression that it was "permanent" somehow like it didn't wear off my bad, but yeah you still run the risk of your body under compensating and not reproducing as many receptors as you lost in the first place. Hell even the PhD's haven't nailed down that science 100 percent. Was just saying it seemed too risky to be worth it IMO

 

[TSLexi]

Well, yeah, that's kinda what I was trying to get at. I thought you were under the impression that it was "permanent" somehow like it didn't wear off my bad, but yeah you still run the risk of your body under compensating and not reproducing as many receptors as you lost in the first place. Hell even the PhD's haven't nailed down that science 100 percent. Was just saying it seemed too risky to be worth it IMO

Yeah, I was wondering why you thought I didn't understand what irreversible receptor ligands were.

 

[DelRi0]

Nothing personal against you brother just didn't know your background and knowledge. Glad to have another BL'er on an enlightened level! .... But still... I don't think it'd work as well as the theory sounds lol :D

Who knows though, I've been wrong many times before. Maybe put out a thread specifically calling for users of irreversible agonists and get some first hand experiences?

 

[Cotcha Yankinov]

I think you would receive more of an effect from a ligand that is constantly binding/detaching because the down stream signaling the results in pain relief happens every time a ligand binds and changes receptor confirmation - normally ligands bind and unbind all the time, while an irreversible agonist would only activate the receptor once until the receptor is recycled.

Irreversible antagonists on the receptors responsible for producing pain would be much more effective.

 

[Pilll_head]

I do research in the drug industry and we do not design medicines that are irreversible agonists (or antagonists) because they are almost guaranteed to be toxic. The only time you want an irreversible interaction is if you are targeting a virus or bacteria and you want to wipe it off the face of the earth. For host (i.e. human) pharmacology you want reversible interactions. The opioid receptor is known as a GPCR or a cell membrane receptor and so they sort of "turn over" meaning that as some get internalized into the inside of the cell others emerge to take their place but irreversible binding would completely disrupt their proper function.

 

[TSLexi]

I do research in the drug industry and we do not design medicines that are irreversible agonists (or antagonists) because they are almost guaranteed to be toxic. The only time you want an irreversible interaction is if you are targeting a virus or bacteria and you want to wipe it off the face of the earth. For host (i.e. human) pharmacology you want reversible interactions. The opioid receptor is known as a GPCR or a cell membrane receptor and so they sort of "turn over" meaning that as some get internalized into the inside of the cell others emerge to take their place but irreversible binding would completely disrupt their proper function.

This is what I wanted to hear. Now I know!

I was studying immunology at university, and I wanted a career in drug discovery for a biopharmaceutical company. But then my life took a different course. What exactly do you do in your research?