Opioid potency/molecular complexity, inversely proportional to euphoric potential.

[fastandbulbous]

^ The degree of analgesia is in a round about way linked to the euphoria as opiates don't effectively block pain, but prevent the emotional response to pain (fear being the main one). the fear of pain being by far the biggest contributor to pain's distressing effects

 

[sarbanes]

^ The degree of analgesia is in a round about way linked to the euphoria as opiates don't effectively block pain, but prevent the emotional response to pain (fear being the main one). the fear of pain being by far the biggest contributor to pain's distressing effects

No doubt, and their are of course, monthly journals devoted to this topic. They talk about all types of different pain (wind up), and lots of other stuff I have never heard of. That is why I cringe when I hear experts arguing about "the cause" or "reason" for this and that, when in reality, it is probably a complex, dynamic tapestry of millions of real time interactions and chaos, weaving a highly complex portrait of the current situation (hope that makes some sense), and not one or two, or even 100 reasons. Why do we have so much oversimplification? Maybe the way I asked the question begs a simple answer, among other factors. tnx 4oh putting up w/ the rant.

 

[Smyth]

The binding affinity of ohmefentanyl stereoisomers for mu-opioid receptors and the effect of chronic ohmefentanyl stereoisomers pretreatments on intracellular cAMP formation were investigated in Sf9 insect cells expressing human mu-opioid receptors (Sf9-mu cells). Competitive assay of [3H]ohmefentanyl binding revealed that these isomers had high affinity for micro-opioid receptors in Sf9-mu cells. Isomer F9204 had the highest affinity for mu-opioid receptors with the Ki value of 1.66 +/- 0.28 nM. After pretreated Sf9-mu cells with increasing concentrations of these isomers for 6 h, addition of naloxone (1 microM) precipitated an overshoot of foskolin-stimulated cAMP accumulation. The ability of these isomers to induce cAMP overshoot differed greatly with the order of F9202>F9205>F9208>F9206>F9204>F9207. Of these isomers, F9202 was 2.7-fold less potent than F9204 in receptor binding affinity, but 71.5-fold more potent in ability to induce cAMP overshoot. These results suggested that there was a significant stereo-structural difference among ohmefentanyl stereoisomers in ability to induce naloxone-precipitated cAMP overshoot in Sf9-mu cells.

Yeah but pharmacology like in the above abstract still makes very interesting reading. Apparently this is indicative of the high physical dependance liability of F9202 relative to F9204. Although if you read more of the abstracts it appears both isomers show activity in the CPP paradigm.

 

[sarbanes]

That stuff is far beyond my comprehension!

 

[leungkachong]

^ The degree of analgesia is in a round about way linked to the euphoria as opiates don't effectively block pain, but prevent the emotional response to pain (fear being the main one). the fear of pain being by far the biggest contributor to pain's distressing effects

This is only partially true. Pain transmission via the ventral funiculus (spinothalamic tract for pain/temperature info, where they used to perform tractotomy to stop horrid pain) is also inhibited by opioids directly.

Euphoria, emotional response to pain, and nociception sent by fast (A-class, fat and myelinated) neurons in the spinothalamic tract are ALL altered by opiates through mu-opioid agonism, BUT they key here is that functional specialization/regionalization in the brain complicate things. The ability to cross ependymal BBB cells as measured by the octanol:water coefficient (and brain uptake index, which no-one here ever mentions) is only the surface on wackyness. Epithelial cells are not all the same, and some evidence says different drugs may cross differentially depending on what arteries feed different gross brain areas, look up leaky epithelial cells). The nuclei (neuroanatomical nucleus, not a cellular nucleus) end up having different threshold concentrations and dose-response curves because of excitatory and inhibitory modulation for different ligands. Etc, etc, etc.
--------------------------------------------------

I'll stop blabbering on but, if you are interested and want to go on a wikipedia-fest:

-Euphoria is mediated by the VTA for opioids (also complicated by the GABA "switch", where opioids seem to stop needing to act on the GABA inhibitory neurons, and work directly on the DA after entrainment)
-"Emotional" responses to pain by the PAG (periaqueductal grey, ventrolateral area which can be stimulated electircally to produce a nod-like posture AKA quiescence)
-Actual pain transmission via the spinothalamic tract in the ventral funiculus.
------------------------------------------------------

Also, I'm going to be an information pirate and share an image that I'm sure a lot of you will enjoy which will kind of highlight your idea F&B (although I did just semi-refute it). It graphs octanol:water coefficient vs brain uptake index. This was the first study to do this, so the data was ancient but mini-revolutionary.

-You can compare heroin and morphine on there to see that even though heroin and morphine have a similar octanol:water coeff., they are taken up by brain tissue very differently.
-It shows why diazepam gets sucked up by fat tissue, and therefore has a cumulating effect.
-And it shows also how saying things like DA "doesn't cross the BBB" is a little simplified.
-Also, it shows how L-dopa uses transporters to completely not fit the trend.

 

[fastandbulbous]

Yeah I know brain uptake isn't directly linked to 1-octanol:water partition coefficient due to active uptake and facilitated diffusion. Does surprise me though that diamorphine is only a bit more lipid soluble than morphine though. L-DOPA does I believe use facilitated diffusion (or is that alpha-methyl DOPA?)

 

[haribo1]

^Just a note, wasn't diconol so euphoric because of the cyclizine in it?

 

[canucklehead]

Ummm personal experience Fentynal 75mg patches never did a thing either for euphoria nor pain nor make one sleep. and I would take/use up to 375mg a day..but then again I didnt bang it or eat it... hmmms. and then the morphine take doses of anywhere from 300 to 600mg a day and straight orally , 99% experience great euphoria and also does wonders for my pain.

 

[sarbanes]

^Just a note, wasn't diconol so euphoric because of the cyclizine in it?

My hypothesis is that the extreme euphoria is also accompanied by an equally extreme H2 release, and the itch really detracted from the high a good bit. Having a central antihistamine like that would not only enhance opioid activity, but would probably prophylactically prevent the itch before the cascade of mast cells break open. Seems to make sense on the surface.

 

[sarbanes]

acetyl leaving

Yeah I know brain uptake isn't directly linked to 1-octanol:water partition coefficient due to active uptake and facilitated diffusion. Does surprise me though that diamorphine is only a bit more lipid soluble than morphine though. L-DOPA does I believe use facilitated diffusion (or is that alpha-methyl DOPA?)

hey fast,

maybe it is the rate of leaving (acetyl from morphine moiety) which is key here, and not just lipo solubility/diffusion. I don't know if the acetyl moiety here technically is a "leaving" group (in the strict sense), but couldn't that be a real factor? tnx

 

[fastandbulbous]

^Just a note, wasn't diconol so euphoric because of the cyclizine in it?

Well cyclazine does bog all for methadone (or morphine, but that's chemically different and an antihistamine is more than just an antinausiant when it comes to morphinans - the above mentioned, dreaded itch), and I'd think if it was due to the cyclazine in diconal that all the diphenylheptanes would be made more euphoric by it

 

[haribo1]

^There are hotspots in the UK where people prescribed methadone ARE shooting cyclizine. The stuff is a bit harder to get, but still fetches 1-2 quid per 50mg tablet. I've got some research somewhere in which all the 1st generation antihistamines were tested to see if they re-enforced opiate usage and they all did. I will just find it...
Oh, and according to Peter McDermott, cyclizine DOES add to morphine. He was given cyclimorph to help get him off opiates and he noted the mad rush due to the cyclizine.

 

[sarbanes]

^There are hotspots in the UK where people prescribed methadone ARE shooting cyclizine. The stuff is a bit harder to get, but still fetches 1-2 quid per 50mg tablet. I've got some research somewhere in which all the 1st generation antihistamines were tested to see if they re-enforced opiate usage and they all did. I will just find it...
Oh, and according to Peter McDermott, cyclizine DOES add to morphine. He was given cyclimorph to help get him off opiates and he noted the mad rush due to the cyclizine.

Its funny you can buy 100 50Mg Meclizine tabs at Costco for like $3, but cheapest I seen 100 50Mg Cyclazine is like $60 (Froogle). Maybe there is a big diff in pharmacology? Just a bit puzzled. Feel free not to comment directly to me, since my breath is so bad. Just refer to me in 3rd person, why don't you all, LOL!

 

[haribo1]

^Meclizine would be more costly to make, looking at the molecule. I've seen 100 for 20 Euro including delivery, so it's still not so expensive, you just have to know where to look. Here is one paper on the methadone<->cyclizine research. Check it out F&B. Basically, people on methadone cane the cyclizine...

Link

 

[Smyth]

Nice work guys although it is now time that we move our discussions to special encrypted invite-only forums so that these closely regarded secrets are not broadcast across the public domain. Hit me up on aim if you are interested in gaining access. However, only the élite need apply.

 

[sarbanes]

Nice work guys although it is now time that we move our discussions to special encrypted invite-only forums so that these closely regarded secrets are not broadcast across the public domain. Hit me up on aim if you are interested in gaining access. However, only the élite need apply.

I am anything but "Elite", so please count me out.
http://72.14.203.104/search?q=cache...+Elite+bar++Broadway&hl=en&ct=clnk&cd=1&gl=us

But I see certain avatars (black punisher leather whip types) who probably are quite "Elite".

Oh, and that guy "Zed", from Pulp Fiction, the guy with the chopper called "Grace". That guy was most deffinately "Elite". ROFL

Know what I mean?

 

[adder]

Good candidates would be lower potency homologues (simple alkyl) of the benzimidazole type, tramadol, and ketobemidone (and lower potency analogs), and several in the methadone series (perhaps Dipipanone). I have noticed these correlation time and again.

Tramadol "euphoria" is in a large degree due to action on other receptors except opioid to start with and ketobemidone analgesic doses are lower than recreational ones compared with morphine from what I recall.

More scientific theories please. Even if this were to be true, you should let us see some papers with an explanation in what way this would work.

 

[sarbanes]

Tramadol "euphoria" is in a large degree due to action on other receptors except opioid to start with and ketobemidone analgesic doses are lower than recreational ones compared with morphine from what I recall.

More scientific theories please. Even if this were to be true, you should let us see some papers with an explanation in what way this would work.

If I remember correctly, the relatively larger gap between effective and euphoric dose w/ ketobemidone (vs morphine, for instance), was theorised to be due to its NMDA antagonistic properties. Sorry, I'm not going to cite studies on this one. I think my original hypothesis may have been overly obtuse in any event. With tramadol, it all eventually boils down to DA in NAc, like so many other things. And yes, tramadol's (&M1's) main actions are seocndary, but primarily u-opiate agonism. If I am not mistaken, tramadol type are specific to only this one type receptor, and only one subtype within. Maybe someone else can add here?

Now, although my original hypothesis may have been flawed, I stand by what I said about the word Elite!

 

[haribo1]

Ketobemidone has been proved to have NMDA antagonist properties. Thats why it's effective for both viceral & neuropathic pain. I've read that statement on analgesic to recreational doses being larger than morphine. Well, I snorted 30mg and was as high as a kite, I wouldn't be very high from 30mg of morphine.
I'm certainly not elite either so I will stay put

 

[Aidan of TCC]

Maybe I'm in over my head here, but to me it sounds like this thread is failing to appreciate the complexity of opioid receptor subtypes and the fact that each of these compounds has a unique binding affinity profile across those subtypes...

For instance, say opioid agonist A has a 5 fold MOR affinity gain over opioid agonist B, which sounds super enough that you just might overlook a 7 fold KOR affinity. Since KOR agonism produces dysphoria, opioid A would likely produce LESS euphoria than opioid B, despite increased MOR affinity...

Of course that's an enormously oversimplified example that doesn't even tip the hat to gamma, delta or sigma opioid receptors, nor does it even cover a respectable fraction of MOR and KOR function.

I guess my point is, you can't boil "potency" down so simply, it's a very complex interplay, as others have mentioned it even extends into the realm of histamine and NMDA receptors.