Why is there an incomplete cross tolerance between opioids?

[kratom luver]

If you use a given opioid, say methadone, and want to switch to another opioid e.g. oxycodone, you would have to lower an equianalgesic dose to take into consideration the incomplete cross tolerance between these two opioids. Why is there an incomplete cross tolerance?

 

[Nagelfar]

I would suppose the body is sensitive to the difference in mode of action between the two opioids and can't fully adjust accordingly as it hasn't been exposed to the specific mode of action, structure of the molecule of the other opioid.

 

[wungchow]

Not regarding activity at other receptor sites (nmda, k-opioid, etc.) there a lot of opioids that activate the mu-receptor by binding to different protein residues. For example, fentanyl and methadone have structural elements that bind to distinct regions on the mu-opioid receptor. Thus, they are cross tolerant, but incompletely so.

 

[The Monkey Mantra]

^^ Please explain why it matters what region they bind on if both produce the same result. If the receptor is gonna change conformation and cause the release of Gi to turn off adenylate cyclase (perhaps the first step in opiate action subject to tolerance) it doesn't matter what residues it binds on, does it? Every step down the line is pretty much the same. They don't have "different specific modes of action", as Nagelfar posited. Now, some opioids cause immediate internalization and the like, so there's a bit of a difference, but is that implicated in the presence or lack of cross-tolerance?

Anyone care to step in on this one?

 

[MurphyClox]

I'm not so sure about the opioids but I'm convinced that with other classes of psychoactives there are indeed "different specific modes of action". This is called 'functional agonism/antagonism'.

Depending on the structure of the ligand the receptors can respond with different signal cascades and, therefore, lead to different physiological responses. I think that it is absolutely possible with opioid-receptors, too, as these are just some else GPCRs. The example that came to my mind is the 5HT2A-receptor, which is known to be able to induce at least 3 different intracellular signaling pathways. Not all of them lead to hallucinations. This kind of diversity on the second-messenger level is, therefore, not uncommon.

The extend to which a compound can (de)activate one pathway, while another one chooses a different way, can IMO lead to incomplete cross-tolerance.

Peace! Murphy

 

[The Monkey Mantra]

Jeez, thanks Murphy! That's fascinating! So that implies that there are multiple possible "activated" conformations of a receptor!

Do you know anything about how opioid receptor dimers and trimers might play a part in this? Y'know, like a hybrid mu-kappa heterodimer? Maybe some ligands produce different responses based on what the dimerization is. My knowledge of the subject is incredibly limited, so check this out:

http://www.aapsj.org/view.asp?art=aapsj080118

 

[MurphyClox]

So that implies that there are multiple possible "activated" conformations of a receptor!

Indeed!

Sorry, but my knowledge ends here, too. Apart from the fact that lots of GPCRs seem to be constitutionally active as homodimers (dunno exactly about heterodimers, never heard about trimers), I can't say much more. But I will have a look tomorrow... AFAIK, monomors of GPCRs are not active, i.e. not working. There have to be always 2 of 'em.

Peace to ya! Murphy

Interestingly, among all possible heterodimeric combinations mentioned in the linked article, I couldn't find k-µ but everything else...

 

[MurphyClox]

This could be helpful (if you have access): The Journal of Neuroscience 2000, 20, RC110

Unfortunately, it deals solely with µ-delta-dimers.

"Heterodimerization of mu and delta opioid receptors: A role in opiate synergy."
Gomes I; Jordan B A; Gupta A; Trapaidze N; Nagy V; Devi L A
PubMed ID 11069979
AN 2001121551

Abstract

Opiate analgesics are widely used in the treatment of severe pain. Because of their importance in therapy, different strategies have been considered for making opiates more effective while curbing their liability to be abused. Although most opiates exert their analgesic effects primarily via mu opioid receptors, a number of studies have shown that delta receptor-selective drugs can enhance their potency. The molecular basis for these findings has not been elucidated previously. In the present study, we examined whether heterodimerization of mu and delta receptors could account for the cross-modulation previously observed between these two receptors. We find that co-expression of mu and delta receptors in heterologous cells followed by selective immunoprecipitation results in the isolation of mu-delta heterodimers. Treatment of these cells with extremely low doses of certain delta-selective ligands results in a significant increase in the binding of a mu receptor agonist. Similarly, treatment with mu-selective ligands results in a significant increase in the binding of a delta receptor agonist. This robust increase is also seen in SKNSH cells that endogenously express both mu and delta receptors. Furthermore, we find that a delta receptor antagonist enhances both the potency and efficacy of the mu receptor signaling; likewise a mu antagonist enhances the potency and efficacy of the delta receptor signaling. A combination of agonists (mu and delta receptor selective) also synergistically binds and potentiates signaling by activating the mu-delta heterodimer. Taken together, these studies show that heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have important clinical ramifications and may provide new foundations for more effective therapies.

 

[MurphyClox]

I can't find any publications mentioning µ-kappa-dimers. These seem to be still unknown...

 

[The Monkey Mantra]

Thanks, Murph. I'll peek around. I coulda sworn I came across something mentioning them existing as *tri*mers, too... But I dunno. Maybe that mu-kappa thing just popped out of my head with nothing behind it.

Oops! Here it is!

This guy demonstrates that all opioid GPCRs can form heterodimers and shows the existence of mu-kappa receptors:

http://molpharm.aspetjournals.org/cgi/content/full/67/6/2173

He also mentions that opioid GPCRs won't form dimers with non-opioid GPCRs. Too bad, 'cause that woulda been really interesting.

 

[Sentience]

Mdfg

 

[Hammilton]

As I recall, mu1-CB1 dimers have been found to exist (and I thought they were implicated in the ability of naloxone to block cannabinoid induced analgesia).

 

[seep]

impartial cross tolerance is very real

seems to be the opposite of incomplete cross tolerance. Impartial = not partial ≈ total = complete ≠ incomplete

 

[Sentience]

xcv

 

[Hammilton]

impartial is obviously not the right word because we're talking about cross tolerance that is partial, ie, not complete.

 

[Sentience]

It is my experience as well that when switching to another opiod, using an equal analgesic conversion might dose me too high.

 

[tamtoot]

a little bit offtopic, but here is some interesting info about CB1 dimers:

The introduction of two concepts, “local module” and “receptor heteromer”, facilitates the understanding of the role of interactions between different neurotransmitters in the brain. In artificial cell systems, cannabinoid CB1 receptors form receptor heteromers with dopamine D2, adenosine A2A and μ opioid receptors. There is indirect but compelling evidence for the existence of the same CB1 receptor heteromers in striatal local modules centered in the dendritic spines of striatal GABAergic efferent neurons, particularly at a postsynaptic location.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635338/