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Where are endorphins stored?

Muzda Jonxx

Muzda Jonxx

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Joined
Jan 14, 2014
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It's all in the title really. I've been rattling for almost a week now, so think about endorphins frequently. Here's what I've thought..

If I take opiates, they get released into my blood and I get high and it feels rather lovely.

If I have sex, I have an orgasm and feel rather lovely.

The implication being, an orgasm causes some system to flood the brain with endorphin. The question is, where is it released from. It's like we've all got a little biological stash bag.

And - secondary bonus question - natural endorphins are hella intense but very short lasting. Where would it rank on the opiate strength chart? And if we could synthesis and inject it, how much to overdose?

These are my non-biological musings, any input welcome!
 
It doesn't appear that endorphins are responsible for the pleasurable effects of orgasm. If that was the case, then people taking naloxone or naltrexone would become anorgasmic, but that doesn't seem to be the case. In addition, studies have shown that naltrexone can actually enhance orgasm:

http://www.ncbi.nlm.nih.gov/pubmed/11395188
http://www.ncbi.nlm.nih.gov/pubmed/199128

Endorphins, like most other transmitters, are stored in vesicles within the presynaptic terminals of neurons, and are released in response to action potentials.

Endorphins are peptides and most are inactive when injected because (a) they are rapidly degraded by enzymes (peptidases) in the blood, and (b) most peptides have difficulty getting into the brain.
 
Do we have much knowledge on what mediates the pleasureable effects of orgasm, or what brain region(s) or cells are most involved?
 
Beta-endorphin is actually 'stored' as a pre-propeptide, proopiomelanocortin, this is cleaved by peptidases and is broken down into multiple fragments with very different effects, such as ACTH, beta-endorphin and others.
 
Interesting stuff, thanks guys. And does anyone know, have any crazy scientists every actually synthesised any of this? You'd have thought they would have tried..
 
Idon't know about crazy ones, but autie ones...have been EXTREMELY tempted to synth beta-endorphin and leu-/met-enkephalin.

WhatI'd really like to try are selective agonists for the epsilon site.I know there are some kappa agonists, I think it might be bremazocine or cyclazocine that are epsilon-OR agonists, but kappa and mu-OR agonists also. I'm happy enough about the latter without taking antagonists (which I CANNOT do, for I am thoroughly physically dependent on pain meds for a buggered knee, the other knee is getting there plus bilateral trochanteric bursitis. I very very nearly did actually, because my stalker cannot produce enough ACTH and I by now must have put a couple of years worth of research into trying to find selective ACTH receptor agonists of nonpeptidic nature for her. (might sound odd ,given shes a self-confessed stalker of me but I love her dearly, and indeed value her life far more than I do or even ever have done my own. She means the world to me, and I'd 'happily' put myself through the kind of tests inflicted on lab animals if it meant that I could render her aid. If organ donation would have saved every penny I have for a flight to where she resides currently so as to make mine available for transplant. If it killed me doing it, so be it, if it meant her life is more comfortable.)

Thats how I learned about endorphin and its storage, in a manner of speaking, as proopiomelanocortin. Its cleaved off from the propeptide on demand, that same peptide has about 4 different ways of being cleaved to different neurohormones and other things besides, like beta-endorphin. I still want to try slamming a proper full dose IV. Although the small one tried really didn't last long. Almost like an orgasm in that its gone as soon as it arrives. About time for a rush thats it, reminds me most of remifentanil, not qualitatively but quantitatively due to its incredibly short duration of action. A cocktail of peptidase inhibitors with it might be nice though, although still do not expect it to last long. I want to try the enkephalins more however as those I haven't even tasted.

Slight derailment-are there any TRULY selective agonists, antagonists, partial agonists, full or partial inverse agonists for either the epsilon OR or the lambda OR binding site? Otherwise the only hope I have of trying an epsilon agonist uncontaminated by other effects of OR agonists is to take a kappa antagonist with one of those mixed KOR agonist/epsilon-OR agonists thereby allowing only the epsilon-OR mediated effects to shine through. And KOR antagonists might be alright anyway given agonists are, or at least can be dysphoric and fucked up shit to use the technical, sciencetificey terninology=D Since KOR agonists inhibit DA release. Silent antagonists, blocking dynorphin binding or inverse agonists if such exist for KORs might well be quite pleasant.

Although at least for MOST clandestine and/or hobbyist chemists/biologists peptide synthesis whilst hardly difficult from a technical/procedural POV does fall far outside the realms of what those chemists and their wannabe, cook-book hangers-on
just because for say, those used to doing the oximation/beckmann/hoffman degredation on voldemelon, or the usual routes to the essential amphetamines from their corresponding phenylpropenoids derived from the correct plant and/or seed oils is quite different. I doubt totally that I myself would bee incapable of getting my waggledance on and managing linear peptides of modest length given a suitable starting aminoacid, after all most of it is just protect, deprotect, protect, deprotect. Nothing special, just totally outside the sphere of experience of most wasps and many bees.

There is one endogenous peptidic agonist that truly does intrique me however, biphalin.

Whilst at first it appeared to me as though it was of a potency that would have ruled out utterly and absolutely (several times more potent than etorphine) it turns out this is by intracerebroventricular administration (mice) but its only some several times more potent than morphia when given via the IP route. And presumably that also follows through IV, subcut and IM routes, and assuming activity, rectally, Reported not to produce dependenxy or tolerance. Of course, I'm going to take that with a portion of NaCl measured via a bilateral digital grip, but low or very low dependency/tolerance potential is far more believable.

That hydrazine bridge is less than appetizing but considering that its of at least pretty decent potency it might just be permissible.

https://en.wikipedia.org/wiki/Kyotorphin This too looks incredibly interesting, and as a dipeptide then it should be pretty damned easy as hell to synthesize, far more so than fucking about doing the synthesis of multiple-AA cyclopeptide
 
Wow! Epic post! I'm intruiged about your relationship with your stalker. But, back to topic.. Thanks for writing that up, my tiny mind could just about keep up with your analysis and explanation. Really interesting that it's cleaved as required from a peptide that can also be other compounds if needs be.

I wonder what it is that causes the glorious sensation to be over as soon as it begins, as you put it (paraphrasing a touch). If someone could find a way around that mechanism, they'd be onto something truly special. Unfortunately I have no real knowledge or background in this, so what I'm on about is probably laughable from a biochemistry perspective. It'd be nifty cool to have a 5 minute orgasm though (although probably quite exhausting).
 
They are stored in large dense core vesicles at presynaptic terminals in a neuron.
 
I thought they were created by the ribosomes in the soma and stored there, then tansported via microtubules to the terminal
 
Hey limpet, I have a friend on here who I suspect of having POMC issues (maybe a deficit or shift in cleavage??) - any suggestions on ways to modulate POMC/POMC cleavage in any way shape or form?
 
Well I haven't looked into the CREATION of POMC, but beta-endorphin is indeed created on demand from this propeptide and cleaved off as and when it is needed.

As for my stalker well, I REALLY, REALLY really would give anything at all, anything upon the face of this earth to be back dating her again.
Otherwise, whilst I'll give none of her personal or personally identifying details whatsoever, because I have the very greatest possible respect for her ladyship, and with all my heart, I adore her in ways that utterly and comfuckingpletely defy description in my native language, my second language, or indeed third, fourth, fifth sixth etc. Nothing could possibly even come close to giving an impression of how much I love, respect and honor her. I'd give my own life for her without a seconds hesitation if ever it were
necessary.

But shes just under 50, three (grown) kids, one of them autistic like she is, but not as far as I know, as much so as she is. But shes whipcord-thin, pale skinned, white of course, but on the really pale side, dark brown ALMOST black hair to light black, hazel eyes, classic autism, intelligence level exceptionally high to extreme, and an accent that just...wow...mmmmmmmm sends shivers down my spine just thinking about hearing her speak. The cutest pointy cheekbones too, any time I see an actress on TV with
ones similar I cannot help myself but get those shivers right through me. Shes only the second person I have ever dated other than one of my two ex-fiancees. not the older of the two, the other one, but her, I last saw when she was 14, again, she too was classically autie (although I did once date another girl who knew my ex-fiancee, who again, Kanner's&MR by neurotype, long, tall, beanpole-slim but curvy figure, dark hair, spesh as hell, and damn if she wasn't cute enough to make newborn kittens hang themselves in shame). And fucking hell I miss her (ex fiancee, not the MR/kanner's girl, although I do, I do miss her too, she was sweet, kind, loving and very, very pretty:)), every damnable fucking day I miss her so deeply its like having strips of skin cut free and torn off, piece, by piece, by piece. But only the second person EVER who I have ever known, who I've ever felt anything like the attraction to and love so deeply for, and I doubt very much indeed there will ever be another. So, chances are, that means a sexless and relationshipless, loveless life for me, for the rest of my days. Because I cannot settle for less.
 
Limpet_Chicken said:
Well I haven't looked into the CREATION of POMC, but beta-endorphin is indeed created on demand from this propeptide and cleaved off as and when it is needed.

As for my stalker well, I REALLY, REALLY really would give anything at all, anything upon the face of this earth to be back dating her again.
Otherwise, whilst I'll give none of her personal or personally identifying details whatsoever, because I have the very greatest possible respect for her ladyship, and with all my heart, I adore her in ways that utterly and comfuckingpletely defy description in my native language, my second language, or indeed third, fourth, fifth sixth etc. Nothing could possibly even come close to giving an impression of how much I love, respect and honor her. I'd give my own life for her without a seconds hesitation if ever it were
necessary.

But shes just under 50, three (grown) kids, one of them autistic like she is, but not as far as I know, as much so as she is. But shes whipcord-thin, pale skinned, white of course, but on the really pale side, dark brown ALMOST black hair to light black, hazel eyes, classic autism, intelligence level exceptionally high to extreme, and an accent that just...wow...mmmmmmmm sends shivers down my spine just thinking about hearing her speak. The cutest pointy cheekbones too, any time I see an actress on TV with
ones similar I cannot help myself but get those shivers right through me. Shes only the second person I have ever dated other than one of my two ex-fiancees. not the older of the two, the other one, but her, I last saw when she was 14, again, she too was classically autie (although I did once date another girl who knew my ex-fiancee, who again, Kanner's&MR by neurotype, long, tall, beanpole-slim but curvy figure, dark hair, spesh as hell, and damn if she wasn't cute enough to make newborn kittens hang themselves in shame). And fucking hell I miss her (ex fiancee, not the MR/kanner's girl, although I do, I do miss her too, she was sweet, kind, loving and very, very pretty:)), every damnable fucking day I miss her so deeply its like having strips of skin cut free and torn off, piece, by piece, by piece. But only the second person EVER who I have ever known, who I've ever felt anything like the attraction to and love so deeply for, and I doubt very much indeed there will ever be another. So, chances are, that means a sexless and relationshipless, loveless life for me, for the rest of my days. Because I cannot settle for less.
Click to expand...

I totally and completely understand. I was lucky enough to meet a beautiful lady who was every bit as crazy, fucked up and extreme as I am. I even married and had two kids with her. I shall love her forever. We'll always be the best of friends, but there's no way we can ever be together again. It's just too dangerous. Cosmic joke, if you ask me. I'll never meet another like her.
 
Me, intense?


Muzda...I know how you must feelngere

I haven't set eyes on one of the two girls I've been engaged to since she was 14, but to this day I still burn up like crazy just thinking about the sound of her voice as she used to call out to me when we met up to spend our time together, and the way it felt ,when she'd throw herself full-force at top speed into me and we'd wrap our arms around each other and generally try and squeeze the life from each other, or how she'd hold us steady while I skinned us a joint in the midst of a howling storm, where neither of us alone could properly stand against the wind. She kept us both firmly on the ground, anchored to a lamp post near this park, that we went to after to smoke our J and drink cheap, shitty cider. Fucking nasty shit, but it was WHO I was drinking it with that makes all the difference, makes it something to remember and treasure from her youngest teen days right up to now, where I'm 30. God....I fucking miss her so intensely. that girl, her face, her cute as hell spesh-sounding voice, her accent, they all haunt my dreams. Cazzie, her name was. Rabid trek fan, bet she still has the star trek encyclopaedia I gave her. I hope she does, because it'd mean that to this day I stand at least some chance of one of my actions bringing her happiness, and I can think of next t to nothing that would mean half as much to me.

And heh, the way we met, she shoved herself against me at a paintball game and frenched me...don't think she;d even given me her name at the time. Gorgeous, gorgeous wonderfuckingful girl. Special in every way. If I am honest after her and my stalker, I am pretty much certain I won't ever date again. MY ex? her of course I would but otherwise, I'll not be dating again.
 
In a similar note to the topic, the way the endorphin system works is that, since they're broken down into longer chains to have their effect, there is no 're-uptake' transporter system for endorphins like there is for monoamine transporters. (though re-assembling them into their original composite structures would be interesting, heh. Future evolutionary step, perhaps? ;-p )
 
Ho-Chi-Minh said:
I thought they were created by the ribosomes in the soma and stored there, then tansported via microtubules to the terminal
Click to expand...

The respective mRNA strand for the endorphins is transcribed from DNA in the nucleus in the soma. The mRNA is then alternatively spliced into mature mRNA strands. This mRNA now goes to a ribosome and is translated into an inactive prepropeptide. As the mRNA is being transcribed, a signal peptidase cleaves off the N-terminal signal peptide (which directed the prepropeptide into the lumen of the rough endoplasmic reticulum) to give a propeptide. The propeptide then goes to the Golgi apparatus, where it undergoes post-translational modifications like endoproteolysis. Then it is packed into large dense core vesicles where it undergoes further modifications like acetylation. They are then transported to the presynaptic terminal via microtubules and then stored there ready to be released.

As for some specific examples related to endorphins, the propeptide POMC (proopiomelanocortin) is endoproteolysed several times by prohormone convertases 1 and 2, to release several peptides including beta endorphin.



F1.large.jpg


met-enkephalin and leu-enkephalin are derived from proenkephalin, and dynorphin is derived from prodynorphin.

Although the different propeptides giving rise to these opioid peptides have wildly different sequences, the opioid peptides themselves have similar sequences, with almost all containing Y-G-G-F at the N-terminus.

512px-Correlaci%C3%B3n_estructural_entre_las_encefalinas_y_la_morfina.svg.png
 
Oh thanks, just what I wanted to know, the juicier in depth details behind the simple cleavage of POMC to their respective hormones and beta-endorphin.

Don't suppose you happen to know how kyotorphin works on the molecular level do you?
 
Thanks aced126, that explains things nicely - and also how it ties in with opiates hijacking the endorphin system. Seems weird to me that poppies would create such a chemical as a so-called 'defence mechanism'. Seems more like an incentive to me.
 
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