Methadone α3β4 Antagonism

[HoldBack]

Given that methadone is a noncompetitive α3β4 neuronal nicotinic acetylcholine receptor antagonist, I'm wondering what, if any, effects can be attributed to this. That is, does a α3β4 antagonist have perceptible effects in humans?

I assume this activity is unimportant to the efficacy of methadone in sustaining abstinence from heroin use but I don't really understand what the significance of the activity is.

 

[DotChem]

^ Very interesting question indeed. Yes it does but the problem is that there are few known truly selective a3b4-nAChR antagonist to use as pharmacological tools to answer that question. So it is hard to tell what is the specific effect of a3b4-nAChR antagonism. Much of known antagonists are also antagonist of other nAChR subtypes like the widespread a4b2 or a7-nAChR. Compounding the problem, in the case of methadone, it is also an opioid receptor agonist, sigma receptor ligand, a weak nmda antagonist and has some central muscarinic acetycholine receptor activity among others. So you can imagine how hard it is to tell whether the effect of methadone is due to antagonism at a3b4 or at other subtypes/receptors or a combination of several factors.

As for the effect of α3β4-nAChR antagonism in humans, a3b4-nAChR has been shown to mediate the development of dependence to morphine as well as opioid withdrawal symptoms but not morphine-induced analgesia. Same with nicotine, alcohol, methamphetamine and cocaine. It seems to be the key for the development of substance addiction. Gene knockout mice lacking the β4 subunit of α3β4-nAChR do not develop tolerance or dependence to morphine compared to their wild-type littermates. They do not have withdrawal symptoms following repeated exposure to morphine unlike their wild-type littermates. Some humans too with genetic mutation on CHRNA3 (the gene coding for a3 subunit of a3b4-nAChR) do not develop tolerance to morphine and do not show opioid withdrawal... (google it or better yet use pubmed to search some of these studies if you interested to learn more).

The few selective α3β4-nAChR antagonist like the peptide conotoxin A has been used (injected directly in some areas of the brain) to block the development of dependence to several addictive substances like opiates, methamphetamine, nicotine..etc but not food, water, sugar or sex. The anti-addiction alkaloid Ibogaine and related is postulated to have antiaddiction properties primarily by antagonism at a3b4-nAChR. The interesting question with regard to blockade of a3b4 and addiction is its relevance AFTER tolerance has developed since its blockade in opioid tolerant still provide attenuation of withdrawals symptoms associated with opioids or methamphetamine.

As for methadone, it is hard to say how relevant is its a3b4 antagonism on its overall bioactivity. Actually some studies actually claim methadone is a partial agonist rather than a noncompetitive antagonist.This was based on facts that cigarettes smokers on methadone smokes twice as much as those on other ORT like bupe. Swicthing them from methadone reduce their need for nictine The idea being postulated is that methadone nicotinic agonism desentize nAChR and thus the need to smoke more.. more nicotine to overcome desentization.. (ref
On the other hand, Bupropion (another a3b4 antagonist) would be more appropriate to assess relevance of a3b4 antagonism in heroin withdrawal and/or abstinence. Since it has fewer off-target interactions than methadone.

 

[Limpet_Chicken]

Very interesting.

Does the alpha3beta4 subtype NAChR fulfill any vital functions necessary to either survival, or not ending up in a hopeless state of misery and living hell (as say a GABAa inverse agonist would)? because it could be interesting what an antisense DNA strand complimentary to a4b4 mRNA might do, using something like a morpholino oligo to knock out the mRNA before translation into protein.

Anecdotally, although methadone is one of my favourite opioids I don't find it very addictive at all, psychologically, whereas say, morphine, dipropionylmorphine (although not so much in the case of H) or 6-monoacetyldihydromorphine, damn, those are psychologically reinforcing as all fuck. I'll have to assess my relative nicotine (of note, there are traces of harmala alkaloids in tobacco aren't there? there certainly seems to be SOMETHING present in actual tobacco which modulates the effect of nicotine, I generally crave a cigar or two after a shot of morphine, but in the case of methadone I don't.

Although it needs to be tobacco, rather than the nicotine alone in the likes of an E-fag (and no I don't mean Dresden), or lozenges, sprays etc. they just don't scratch that itch that a smoke afterr E.g a shot of DPM does.

 

[HoldBack]

^ Very interesting question indeed. Yes it does but the problem is that there are few known truly selective a3b4-nAChR antagonist to use as pharmacological tools to answer that question. So it is hard to tell what is the specific effect of a3b4-nAChR antagonism. Much of known antagonists are also antagonist of other nAChR subtypes like the widespread a4b2 or a7-nAChR. Compounding the problem, in the case of methadone, it is also an opioid receptor agonist, sigma receptor ligand, a weak nmda antagonist and has some central muscarinic acetycholine receptor activity among others. So you can imagine how hard it is to tell whether the effect of methadone is due to antagonism at a3b4 or at other subtypes/receptors or a combination of several factors.

As for the effect of α3β4-nAChR antagonism in humans, a3b4-nAChR has been shown to mediate the development of dependence to morphine as well as opioid withdrawal symptoms but not morphine-induced analgesia. Same with nicotine, alcohol, methamphetamine and cocaine. It seems to be the key for the development of substance addiction. Gene knockout mice lacking the β4 subunit of α3β4-nAChR do not develop tolerance or dependence to morphine compared to their wild-type littermates. They do not have withdrawal symptoms following repeated exposure to morphine unlike their wild-type littermates. Some humans too with genetic mutation on CHRNA3 (the gene coding for a3 subunit of a3b4-nAChR) do not develop tolerance to morphine and do not show opioid withdrawal... (google it or better yet use pubmed to search some of these studies if you interested to learn more).

The few selective α3β4-nAChR antagonist like the peptide conotoxin A has been used (injected directly in some areas of the brain) to block the development of dependence to several addictive substances like opiates, methamphetamine, nicotine..etc but not food, water, sugar or sex. The anti-addiction alkaloid Ibogaine and related is postulated to have antiaddiction properties primarily by antagonism at a3b4-nAChR. The interesting question with regard to blockade of a3b4 and addiction is its relevance AFTER tolerance has developed since its blockade in opioid tolerant still provide attenuation of withdrawals symptoms associated with opioids or methamphetamine.

As for methadone, it is hard to say how relevant is its a3b4 antagonism on its overall bioactivity. Actually some studies actually claim methadone is a partial agonist rather than a noncompetitive antagonist.This was based on facts that cigarettes smokers on methadone smokes twice as much as those on other ORT like bupe. Swicthing them from methadone reduce their need for nictine The idea being postulated is that methadone nicotinic agonism desentize nAChR and thus the need to smoke more.. more nicotine to overcome desentization.. (ref
On the other hand, Bupropion (another a3b4 antagonist) would be more appropriate to assess relevance of a3b4 antagonism in heroin withdrawal and/or abstinence. Since it has fewer off-target interactions than methadone.

Exactly the type of answer I was looking for. Not over my head but not overly dumbed down either.

And the answer is as I expected drugs are too dirty and non selective to really a answer the question.

In my expereience, I find methadone diminishes my fiendish for nicotine. I stopped smoking about 4 months into mmt and it sounds silly but I really did not intend to quit. I still suck on lozenges sometimes but I?d say I eat the vast majority before bed as the methadone is wearing off and have very little interest in the morning after I dose.

And now it makes me wonder if methadone had something to do with quitting because I?ve heard a lot of people at the clinic talk about how they?ve quit smoking. Then again a pack in SF coats like $10 and I go to the trashy clinic in the TL where most the people homeless.

I?m surprised there?s still so much we don?t know about the brain and the interaction of the different receptors. Personally I don?t think they will make it to ?curing? addiction in my lifetime but I imagine it?s possible.

 

[DotChem]

α3β4-nAChR and opiates tolerance and withdrawals

The α3β4* nicotinic ACh receptor subtype mediates physical dependence to morphine: mouse and human studies
Muldoon et al. Br J Pharmacol 2014, 171(16): 3845-3857 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128047/ $FREE$ article

Methadone agonism/antagonism at nAChRs and smoking:

Methadone's effect on nAChRs--a link between methadone use and smoking?
Talka et al. Biochem Pharmacol 2015, 97(4): 524-549 https://www.ncbi.nlm.nih.gov/pubmed/26231941 $PAYING$ article

Abstract: Methadone is a long-acting opioid agonist that is frequently prescribed as a treatment for opioid addiction. Almost all methadone maintenance patients are smokers, and there is a correlation between smoking habit and use of methadone. Methadone administration increases tobacco smoking, and heavy smokers use higher doses of methadone. Nevertheless, methadone maintenance patients are willing to quit smoking although their quit rates are low. Studies on nicotine-methadone interactions provide an example of the bedside-to-bench approach, i.e., observations in clinical settings have been studied experimentally in vivo and in vitro. In vivo studies have revealed the interplay between nicotine and the endogenous opioid system. At the receptor level, methadone has been shown to be an agonist of human α7 nAChRs and a non-competitive antagonist of human α4β2 and α3* nAChRs. These drugs do not have significant interactions at the level of drug metabolism, and thus the interaction is most likely pharmacodynamic. The net effect of the interaction may depend on individual characteristics because pharmacogenetic factors influence the disposition of both methadone and nicotine.