Opioid Mu Receptors and Drug Dependancy

[Giza]

Why is it that two very potent mu receptor agonists can have two completely different dependancy ratings??? Meaning one can have dependancy levels similar to morphine, and yet another agonist, one that is even a more potent mu agonist, can have a lesser dependancy, far lesser?

Is it because one is a more mu selective than the other, and perhaps its only one of the specific mu receptors that regulates drug dependancy??

Or does it have to do with something completely different?

 

[BilZ0r]

Which compounds are you refering to?

But often it's a matter of pharmacokinetics. If a drug doesn't get into the brain rapidly, it wont be addictive.

But what is this Mu agonist that doesn't cause dependence?

 

[C6H6]

I mentioned the same thing in the ohmefentanyl thread. Opioid pharmacology is still full of wonders!

 

[Giza]

This was in regards to

http://www.ncbi.nlm.nih.gov/entrez/...d&dopt=Abstract&list_uids=10901279&query_hl=2

F9202 and F9204

 

[stvip]

And on the other hand,
http://www.ncbi.nlm.nih.gov/entrez/...ed&dopt=Abstract&list_uids=1824543&query_hl=9

 

[BilZ0r]

Do you know whether the isomers are both selective mu agonists? Could the low dependence isomer be acting at other receptors to induce it's antinocicpetive action, and hence not be a strong mu-agonist at all? You know, other opioid receptors, NMDA receptors, serotonin/noradrenaline receptors?

 

[Giza]

Do you know whether the isomers are both selective mu agonists?

Yes.

(-)-cis-(3R,4S,2'R) OMF (F9202), and (+)-cis-(3R,4S,2'S) OMF (F9204) had similarly potent analgesic action and high selectivity to µ opioid receptor[1], but showed a large difference in physical dependence[2]

[1]: Jin WQ, Wang ZX, Chen J, Chen XJ, Chi ZQ. Analgesic activity and selectivity for opioid receptors of enantiomers of ohmefentanyl. Acta Pharmacol Sin 1996; 17: 421-4

[2]: Guo GW, He Y, Jin WQ, Zou Y, Zhu YC, Chi ZQ. Comparison of physical dependence of ohmefentanyl stereoisomers in mice. Life Sci 2000; 67: 113-20


They go on to say;

The mechanisms that underlie the development of opioids dependence remain unclear. Recent findings indicated that learning and memory and drug addiction shared certain intracellular signaling cascades and depended on activation of transcription factor cAMP-response element binding protein (CREB)

So by the sounds of it, just because something IS a high mu agonist, and therefore euphoric, it does not necessarily mean it is physically dependant, but likely to still be psychologically dependant being that its highly mu selective.

Basically translating in the blunt to cleaner opioids.

 

[BilZ0r]

Sounds like bullshit to me... if it's true, all it means is that the animal models are shit (and by the sounds of things (naloxone-precipitated jumping???) they are).

 

[stvip]

Sounds like bullshit to me... if it's true, all it means is that the animal models are shit (and by the sounds of things (naloxone-precipitated jumping???) they are).

That's quite harsh. If one studies the opioid literature, one soon discovers that a great many beliefs commonly held, even amongst researchers, is actually cast in much doubt. A mu agonist isn't necessarily euphoric. It is not clear that real opioid receptor subtypes (as in distinct proteins) exist. Different strains of the same species can consistently react very differently to the same opioids, as well as intergender differences. There is a very important role to the behavioural-associative aspect in opioid tolerance (in fact, there might be two different types of tolerance, associative and non-associative). Etc. The study I mentioned found an opioid which induces tolerance (with morphine cross-tolerance) but no analgesia. I don't believe it's so unthinkable that an opioid with equal analgesic potential to its enantiomer, but with reduced dependence, can exist. Naloxone-precipitated jumping is a very standard test for opioid dependence, and quite reliable, though this should obviously be further studied (the naloxone jumping when used alone is problematic when testing for interventions that reduce withdrawal symptoms, though).

As for CREB - not really surprising that a long-term change in neuronal signaling involves it.

 

[BilZ0r]

Well sure, there is a lot we still don't know about agonist-direct trafficking, differential desensitization and how these are correlates to behavioural tolerance and hence dependence/withdrawal. I suppose that it could be possible for a drug to bind to a conformational form which supports G-protein activation, but not downreuglation... but I doubt it.

I just plain don't trust most animal models. Animal models for stroke, depression, MS, epilepsy etc are shit.

If you can show me that this drug is a selective mu agonist, doesn't cause mu receptor internalization in primary neuronal cultures and doesn't cause a reduced transduction efficacy in regards to a fast correlate of receptor activation (i.e. electrophsyiology not GTP-gamma-S), then I'll believe you.

 

[stvip]

. I suppose that it could be possible for a drug to bind to a conformational form which supports G-protein activation, but not downreuglation... but I doubt it.

Check out the latest findings about Gi vs. Go signal transduction in morphine tolerance (which has been led to by studying the effects of ultra-low-dose naloxone). Pretty interesting. I'm not an expert on GPCR, but I think it might be possible that different opioids modulate different types of signalling by interacting, or not interacting, with specific amino acids of the protein. There's too much we don't know or understand about opioid tolerance to cast so much doubt about finding an opioid with reduced dependence potential - but obviously it should be studied more.

I just plain don't trust most animal models. Animal models for stroke, depression, MS, epilepsy etc are shit.

MS, stroke - definitely. Epilepsy - don'y know. Depression? Animal models to date have been pretty good predictors for efficacy in humans.
I think opioid testing in animals has also proven pretty reliable, though different species, and even different strains of the same species, have been found to have quite different reactions to the same substances.

If you can show me that this drug is a selective mu agonist, doesn't cause mu receptor internalization in primary neuronal cultures and doesn't cause a reduced transduction efficacy in regards to a fast correlate of receptor activation

Quite the contrary, as much as animal models can be problematic, actually showing reduced dependency in a living being is far better support than any suspected correlate of in vitro biochemistry.
Also, the role of MOR internalization is unclear. Morphine, for example, causes mininmal receptor internalization and desensitization. (some researchers believe receptor internalization is crucial for preventing tolerance).

 

[BilZ0r]

^ Well, it's all about asking whether or not the animal is feeling subjective withdrawal feelings, asking experiemntal animals these questions is pretty hard. Hence, I would denounce the animal model if the animal showed no withdrawal but all the biochemical data pointed to it showing no difference to morphine.

 

[Carfentanilfreak]

Ohmefentanil is an interesting drug with a potency possibly much stronger than Carfentanil. Is there any place on the web that would show a molecular structure for this chemical? It would be interesting to see how its structure compares to other fentanyls.