Research provides new understanding of how heroin affects brain (HEROIN =/= MORPHINE)

[acemonvw]

Well, I'm coming from the perspective of only once having an opiate administered... that was fentanyl when I had my wisdom teeth out to knock me out. I ended up puking afterwards, and actually didn't take any of the oxycodone they gave me. Althought I will say that that was the only time after I'd ever thrown up where I really wanted to eat immediately afterwards...

Anyway, to continue with the discussion, I found an artical by Jason Umans and Charles Inturrisi titled "Pharmacodynamics of subcutaneously administered diacetylmorphine, 6-Acetylmorphine and morphine in mice" where they mention:
"... CNS depressant activity in rats and analgesic activity in cats (Eddy and Howes, 1935) showed that heroin and AM (which is 6MAM, they just used to call it acetylmorphine) were equipotent, suggesting that the effects of DAM (heroin) might be mediated by its metabolite, AM"

The group went on to do more behavioral work showing heroin and 6MAM effects being almost identical in their experiments (in mice).

I also have the paper showing the affinity of each of heroin and its metabolites to the u-opioid receptor, that's titled, "u Opioid receptor-mediated G-protein activation by heroin metabolites: evidence for greater efficacy of 6-monoacetylmorphine compared with morphine."

I think at this point, the most plausible counter-argument one could make is that how do we know that 6MAM isn't just a prodrug for morphine? However, what we find in animal studies is that behavior is correlated with 6MAM levels in the brain when heroin is administered. The morphine levels rise, but much later, so that initial effect is most likely 6MAM.

 

[23536]

Well, I'm coming from the perspective of only once having an opiate administered... that was fentanyl when I had my wisdom teeth out to knock me out. I ended up puking afterwards, and actually didn't take any of the oxycodone they gave me. Althought I will say that that was the only time after I'd ever thrown up where I really wanted to eat immediately afterwards...

I think people who find opiates generally undesirable are lucky. That said, there has been discussion here about fentanyl being significantly less euphoric than heroin and oxycodone.

Do you by any chance know about how the kinetics of the glucuronyl transferases affect the subjective experience of heroin, morphine or codeine? There is a discussion with some unanswered questions in the advanced forum:

http://www.bluelight.ru/vb/showthread.php?t=581384

 

[Nagelfar]

3,6-acetyl-morphine (a.k.a. heroin) is a prodrug of 3-acetylmorphine & 6-acetylmorphine, both of which are prodrugs of morphine. 3AM is inactive & 6AM is active. The binding site on 6-acetylmorphine is the same as on morphine. (This is why heroin is roughly half again as potent as morphine, simple mathematics).

6AM has affinity for Mu-3 receptors but so does the metabolite of morphine, M6G, due again to the 6 position in addition to the binding site behind the 3 position (same binding affinity as morphine)

The lack of relative histamine release in heroin compared to morphine is due to the fact that heroin is not immediately active until deacetylated.

Difference between heroin & morphine? Not very much at all.

 

[acemonvw]

Do you by any chance know about how the kinetics of the glucuronyl transferases affect the subjective experience of heroin, morphine or codeine? There is a discussion with some unanswered questions in the advanced forum:

http://www.bluelight.ru/vb/showthread.php?t=581384

I don't know much about the kinetics of the transferases, but my guess is that their kinetics wouldn't really be a major factor for intravenous administration of heroin because heroin would bypass first pass metabolism and heroin goes straight to the brain to elicit its effects. If one were to take the drug orally, then that's a major difference... but maybe you were asking something else?

Difference between heroin & morphine? Not very much at all.

I don't think I follow you. The difference between heroin and morphine is actually very large. A number of factors would influence this.

A few points:
1) Heroin is extremely lipophilic, it will enter the brain much more rapidly than morphine. (Rate of distribution of a drug to the brain has a major impact on its reinforcing effects)
2) Heroin has lower affinity for the receptor, exactly for the reasons that you mentioned, i.e., binding occuring on the 3 position alcohol group (OH) of morphine.

Also, I could be wrong, but mentioning 3-acetylmorphine seems irrelevant because if it were present it would be a very minor metabolite as the 3 position acetyl group is far more labile than the 6 position acetyl group, and thus its occurrence is rare.

Also important for morphine and heroin binding is the amino methyl group (I forget the position), though I believe this plays a role in their ability to act as agonists vs antagonists.

Why 6AM has a higher affinity for the mu-opioid receptors than morphine does is probably related to the ease at which it can fit in the binding pocket of the receptors. With morphine, it's more able to dock 'inappropriately' at the 6 position, and would have to be rearranged... This is a bit of speculation however.

Last, something I read today was that someone suggested that heroin may bind to different opioid receptors to elicit its antinociceptive effects. I can find the article and let you know what it is if you're interested.

 

[Nagelfar]

I don't think I follow you. The difference between heroin and morphine is actually very large.

"Actually very large" doesn't follow from anything else you put in your response. If the difference between heroin and morphine is "very large" then what is the difference between heroin and (the still exceedingly similar) Oxycodone, or Hydrocodone? The yet more different Fentanyl? the more different yet Tramadol? Salvinorin? a drug with another type of activity like MDMA? etc.

 

[acemonvw]

"Actually very large" doesn't follow from anything else you put in your response. If the difference between heroin and morphine is "very large" then what is the difference between heroin and (the still exceedingly similar) Oxycodone, or Hydrocodone? The yet more different Fentanyl? the more different yet Tramadol? Salvinorin? a drug with another type of activity like MDMA? etc.

I apologize about the ambiguity, however, it did stem from your ambiguity. You said that the difference between morphine and heroin was 'not much at all.' I was merely debating the truth in that statement by giving two points that refute the similarities that you were suggesting, based on quantitative measures done that show significant differences. There are a number of studies showing significant differences between injecting heroin and morphine in behavioral studies as well as pharmacokinetic assays. The differences between heroin and 6MAM using these same measures, however, are 'not much at all," (aka, not significant differences... quantitatively).

The discussion has nothing to do with oxycodone/hydrocodone. The point of contention is: What is the more potent active metabolite of heroin, morphine or 6MAM? I think we would need a completely new thread setting up a matrix of information to go through all of the other drugs that you want to go through. And in making that argument, why stop at the differences between heroin and oxycodone, hydrocodone, tramadol, fentanyl and salvinorin, when you can go on to discuss differences between every drug...

But to bring up oxycodone, it has somewhat odd pharmacokinetics in that its lipophilicity is similar to morphine, yet it reaches the brain much more rapidly. This may be due to active influx, but I'm not not terribly familiar with the data, you're welcome to look at it:
http://dmd.aspetjournals.org/content/34/9/1624.full

 

[Pegasus]

^Thanks for the link.