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selective beta-endorphine reuptake inhibitor?

rangrz

rangrz

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Canada eh, we get milk in bags.
Anyone know of anything with this path of action? I searched and came up with nothing on it. Seems like it might make a) a novel anti-depressant or b) novel painkiller and recreational drug.

Aside from that, its a curiosity I have, so I figure I would ask people more knowldegable then I.
 
There's a such thing as a beta-endorphin transporter?
 
Not only do I know of none, but i am not sure it is a pathway that big pharma has indeed bothered to look at at all as 1 -- yes it may have a anti-depressant effect at the right dose and 2- indeed yes iut may be recreational and hence why they have not bothered due to liklihood for abuse -- and 3-- they may have no existing pharmacore so it is easier to go after those paths that do
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there is this and others to note on the area though:

Serotonin-Mediated Increases in the Extracellular Levels of β-Endorphin in the Arcuate Nucleus and Nucleus Accumbens : A Microdialysis Study
Abraham Zangen, Rachel Nakash & Gal Yadid
Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel
Address correspondence and reprint requests to Dr. G. Yadid at Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.

Abbreviations used : aCSF, artificial CSF ; DA, dopamine ; 5,7-DHT, 5,7-dihydroxytryptamine creatinine sulfate ; DOPAC, 3,4-dihdyroxyphenylacetic acid ; 5-HIAA, 5-hydroxyindoleacetic acid ; 5-HT, serotonin ; HVA, homovanillic acid.
Copyright International Society for Neurochemistry
KEYWORDS
β-Endorphin • Fluoxetine • Microdialysis • Serotonin • Nucleus accumbens • Arcuate nucleus.
ABSTRACT

Abstract : Although the involvement of both endogenous opioid and serotonergic systems in modulation of pain and emotion was suggested, the neurochemical interaction between these systems in the brain has not previously been studied directly. Herein, the effects of the local application of serotonin (5-HT) and fluoxetine (a 5-HT reuptake inhibitor) on extracellular levels of β-endorphin in the arcuate nucleus and nucleus accumbens were assessed in freely moving rats using in vivo microdialysis. The mean basal concentrations of β-endorphin in dialysates obtained from the arcuate nucleus and nucleus accumbens were 259.9 and 143.3 pM, respectively. Specific lesion of the serotonergic system by 5,7-dihydroxytryptamine (5,7-DHT) caused a significant decrease in these dialysate β-endorphin levels. When 5-HT (0.25-5 μM) was added to the perfusion solution, the levels of β-endorphin in the dialysate from the arcuate nucleus increased (186-296% of baseline), in a concentration-dependent manner. In the nucleus accumbens, 0.5 and 2 μM 5-HT in the perfusion fluid did not affect the levels of β-endorphin in the dialysate, whereas 5 and 10 μM 5-HT caused an increase of ~190% of baseline. When fluoxetine (250 μM) was present in the perfusing solution, the levels of β-endorphin in the dialysates from the arcuate nucleus and nucleus accumbens increased two- to three-fold. This effect was not obtained in the 5,7-DHT-lesioned rats. Thus, 5-HT, either endogenously or exogenously delivered, appears to facilitate the release of β-endorphin in the arcuate nucleus and nucleus accumbens. This indication of an interaction between serotonergic and endorphinic systems may be relevant for assessing pain and mood disorder circuits and the mode of action of antidepressant drugs.
 
nuke said:
There's a such thing as a beta-endorphin transporter?
Click to expand...

that's what I was wondering too, actually. I thought they sort of circulated like hormones.

are they hormones? are they actually neurotransmitters?
 
Hmm, I recalled reading something about a transporter, but I could very well be wrong...

in that case, a -ese inhibitor or whatever other pathway that otherwise makes b-endorphin go away/stop acting on the receptor.

thanks for that abstract tho. :)
 
I thought endorphins were a kind of hormones produced in the hypothalamus, or such, when in prolonged exercise or strain. Not that they are stored in neuronal vesicles, and released and possibly reuptaken, in the same manner some neurotransmitters are.

Am I wrong? I don't seem to be able to recall where I've read about it.
 
...and now ya know

The term Endorphin, comes from Endogenous and Morphine as it was found to act like an endogenous classical opiate, morphine, upon discovery

They can be considered NTs, but more appropriately are termed neurohormones and are peptides

Beta-Endorphin is just one of to date over 20 compounds that fit this class

They bind to opioid receptors, though some in ways differing from classical opiates, as they are basically endogenous opioids.
There does indeed exist a specific transport system so in theory one can have assumbly a SERI

Here is one example of a SET:

Biochem. J. (2003) 375 (17–22) (Printed in Great Britain)

Accelerated publication
Identification of a novel Na+- and Cl--coupled transport system for endogenous opioid peptides in retinal pigment epithelium and induction of the transport system by HIV-1 Tat
Huankai HU*, Seiji MIYAUCHI*, Christy C. BRIDGES*, Sylvia B. SMITH† and Vadivel GANAPATHY*1

*Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta GA 30912, U.S.A., and †Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA 30912, U.S.A.

The endogenous opioid peptides enkephalins, dynorphins and endorphins consist of five or more amino acids. These peptides participate in a multitude of biological functions in mammalian cells by interacting with different subtypes of opiate receptors located on the plasma membrane and in the nucleus. Here we report on the identification of a new peptide transport system in the human retinal pigment epithelial (RPE) cells that transports a variety of endogenous opioid peptides with high affinity. We identified this novel, hitherto unrecognized, transport system when we were analysing the differential effects of Tat, the transacting factor encoded by HIV-1, on various transport processes in RPE cells. This transport system is markedly induced by Tat. This opioid transport system is energized by transmembrane Na+ and Cl- gradients and is distinct from any of the previously identified transport systems for opioid peptides in mammalian cells. Free amino acids, dipeptides, tripeptides and non-peptide opiate receptor antagonists are excluded by this newly identified transport system. The affinities of endogenous opioid peptides for this system are in the range of 0.4–40 µM. The identification of the high-affinity Na+- and Cl--coupled transport system in mammalian cells that is specific for endogenous opioid peptides and is induced by HIV-1 Tat is of significance not only to the biology of opioid peptides but also to the pathology of HIV-1 infection in humans.

and link to a use patent for exploiting such:
http://www.freepatentsonline.com/y2006/0019241.html

article about such:
http://www.mcg.edu/news/beeper/Jun22/GanapathyResearch.htm

And lastly an excellent journal article by this researcher with great detail:
http://www.aapspharmsci.org/view.asp?art=aapsj070482
 
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I have read of a couple of bioassay trials of enkephalinease inhibitors on the blacker shade of bluelight, and seemingly they weren't recreational but effective against pain, and potentiating opiates.
 
Neuropeptides are not reuptaken into the cell, they are destroyed in the synapse by proteases or diffuse away. If there's no reuptake, there's no way for a reuptake inhibitor to exist.
 
This is a really old thread and I created one similar asking about a µ-RI and received an answer stating what you just said. However, a chemical could be made in order to inhibit catalyzation through hydrolysis.
 
Hm, you would have to have a chemical that would inactivate the specific peptidases responsible for breaking down endorphins, which would be a very complex task with risky outcomes to say the least.
 
5hToInfinity said:
Hm, you would have to have a chemical that would inactivate the specific peptidases responsible for breaking down endorphins, which would be a very complex task with risky outcomes to say the least.
Click to expand...

Maybe. In some cases, promoting a neurotransmitter's synthesis via enzyme-induction or increasing precursor availability, or inhibiting enzymatic breakdown, can be easily managed via a single compound (see MAOIs and l-dopa). However, I think that you're right in that the outcomes will be risky, as tinkering with such pathways is bound to have clear side-effects, and control over the 'main effect' will be pretty rough.

Also, I'd look over Lux's post again--there IS an uptake system for endogenous opioids, though their presence is limited, so the utility of endorphin reuptake inhibitors might be a bit limited.

ebola
 
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I'm thinking it would be quite dangerous to fiddle with degradation mechanisms for neuropeptides in general because their effects are quite significant in very low concentrations and very low release frequencies. Opioid agonists are already troublesome enough, imagine if there were additional chemicals capable of amplifying their effects.. All hell would break loose. Or heaven, depending on how you see things :P
 
Opioid agonists are already troublesome enough, imagine if there were additional chemicals capable of amplifying their effects.
Click to expand...

Opioid agonists might be so dramatic in effect simply because of how much more powerful they are than their endorphin counterparts. Also, changes to synthesis, catabolism, and reuptake of endogenous opioids shouldn't affect the efficacy of exogenous opioid agonists a great deal since known opioid medications aren't peptides.

ebola
 
Hm, endorphins are released in nanomolar concentrations, opioid agonists achieve their affects at higher concentrations. If reuptake inhibitors were developed, who knows how high you could take those concentrations or how dangerous that would be.
 
A selective beta-endorphin reuptake inhibitor would probably be used for something like anti-anxiety or as an anti-depressant or something along those lines. Recreational potential would probably exist - but since it would be selective to certain receptors - it would probably be low.

A non-selective beta-endorphin reuptake inhibitor would most likely have much more recreation potential because it wouldn't be selective to just certain receptors. This means it would probably bind to the endorphin transporter as well as bind to U, O, and K opiate receptors.

Anyways, Nicotine is an indirect Endorphin agonist - just as amphetamine is an indirect Dopamine agonist.
 
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