Big problem with Pramipexole

[sekio]

How are you measuring the levels of monoamines inside your brain?

 

[Nagelfar]

But the external agonists also not endogenous, have 100 % same molecular structure like the endogenous ?! Also I belive that the external have not exactly the same effect like endogenous.

Generally speaking endorphines are peptides but yes morphine and 6-acetylmorphine are found in the human body just as the metabolites of heroin, in extremely small amounts. These are different than the peptides most often referred to when alluding to endorphines.

 

[AlphaMethylPhenyl]

It can be confusing. Dynorphin is a mu agonist, for instance.

 

[Ovideo_1978]

I don`t understand why Endorphines are not monoamines ?! Also why Serotonin, Dopamine is, and endo not ?! Also perhaps exists a method to create a ERI, adica reuptake inhibitor.

 

[sekio]

Endorphines are not monoamines

... because the very definition of "monoamine" meaning "one basic nitrogen atom". Serotonin, dopamine, adrenaline, and noradrenaline all have one basic amine group present: ergo monoamines. Endorphins on the other hand are complex peptides (protiens), containing many nitrogen atoms.

 

[AlphaMethylPhenyl]

I defer to the authority of sekio on this... but yeah opioids both endogenous and exogenous are long chains of atoms, which girth probably is involved in how they can affect the brain to such an extent, specifically the reward circuit. Monoamines are small, but they still affect volume neurotransmission; the hitch is that dopamine and nor/epinephrine are stimulating chemicals called catecholamines, while serotonin is an indolamine, as is the trace amine tryptamine. Then there are amino acids like GABA, glutatmate, and serine; GABA relaxes and glutatme stimulates, though I believe the former gets metabolized to the latter, in no small part due to (the glial cells called) astrocytes. Acetylcholline is in its own class, but not to be mistaken, is integral for muscle contraction, and it seems, reward. Endocannabinoids aren't well-studied, and to me, represent a sort of enigma. The A2/Cb1 heteromer probably explains part of how caffeine has a slight dissociative effect that seems unique to xanthines vs. classic stimulants.

Blah blah blah

 

[sekio]

Endocannabinoids aren't well-studied, and to me, represent a sort of enigma.

There;s actually been a whole bunch of research on endocannabinoids and the cannabinoid receptor system in the body in the last 10-20 years. Some interesting discoveries include the identity of rhe endogenous CB₁R ligand, anandamide, which turned out to be an ethanolamine amide of a polyunsaturated fatty acid (pretty much as unique as you can get for a drug structure!) The natural enzymes responsible for breaking down endocannabinoids were also elucidated as well as inhibitors for the enzyme. These FAAH (fatty acid amide hydrolase) enzymes degrade the endocannabinoids, so if you block them the end result is a cannabis-type effect caused by the elevated levels of anandamide. Mutations in the gene that result in loss of function result in pain insensitivity and the curious side effect of being wholly unable to experience anxiety. It was discoveres that acetaminophen may produce some of its effects by metabolizing into a compound strucutally quite similar to anandamide, called AM-404. Also, nutmeg (rather, some component in the oil fraction) was finally established as a FAAH inhibitor, which may be tthe cause for its unique intoxication profile, rather than the previous thinking which was "ir is kind of like a deleriant, maybe, but we don't atually know?" Conveniently it lines up with my own experiences with nutmeg - a very stoning, sedating, hashish-like high clearly reminiscent of cannabinoids. There have even been a few research chemicals produced that act as FAAH inibitors, e.g. URB597.

There was a compound known as BIA 10-2474 developed as a FAAH inhibitor which unfortunately caused the worst possible side effect one could expect: rapid destruction of large amounts of brain cells - thankfully only in the group of patients recieving the highest dose, 100mg, investigated in the trial. (There were 84 others who had no negative effects nor brain damage, who took either placebo, 20mg, or 50mg doses.) Due to a series of oversights and failures in the study methodology, the initial tolerability study included a needlessly high dose well beyond the expected theapeutic dose. In addition, the compound was administered to all 5 individuals without a period of observation - by the time the first individual started to show signs of seriously bad shit, the other 4 people had all been dosed and were effectively walking dead. There was also a suggestion that perhaps it had not undergone as rigorous of an animal testing program - had appropriate tests been conducted of high doses in monkeys, the neurotoxic effect would be discovered with no loss of human life. (I'd feel bad for the monkey though) The aftermath of the trial was that one person died and four were hospitalized with severe brain damage (necrosis and haemorrhage) which undoubtedly changed their lives in a massively negative way, if not outright crippling them mentally speaking. It also put a blood colored full-stop on the chapter of that particular compound, and cast some suspicion on other FAAH compounds (which don't have a comparable neurotoxic effect) Aside from that one nasty, the whole field still has plenty of room to expand, so maybe future FAAH inhibitors could find use as painkillers, antidepressants, or even novel recreational drugs..

 

[thegreenhand]

It was discoveres that acetaminophen may produce some of its effects by metabolizing into a compound strucutally quite similar to anandamide, called AM-404

Acetaminophen inihibits COX-2 (and COX-1 actually) an enzyme whose activity has been associated with increased prostaglandin levels. High levels of prostaglandins have been associated with increased stress and inflammation levels. delta9-THC actually induces COX-2 activity whereas acetaminophen inhibits COX-2. I’m not sure if anandamide and the other endocannibinoid’s interactions with the COX enzymes have been identified to date

 

[AlphaMethylPhenyl]

I thought FAGL was also an endo/cannabinoid metabolizing agent

 

[Ovideo_1978]

sekio, I understood, and if the endorphins have many nitrogen atoms , doesn`t exist a reuptake pump ?! Also why only by monoamine cand exista a reuptake pump, and to endo not. Also doesn`t exist presynaptic receptors which give endorphines to postsynaptic receptors ?! Something (presynaptic receptors) must give endorphins to opioid receptors (I think postsynaptic receptors). And when presynaptic and postsynaptic receptors exist, also a reuptake pump exists too. And we can make a ERI medication.
Why does it matter that they are not monoamines ?! poli or mono, normal must be same mechanism.

 

[thegreenhand]

sekio, I understood, and if the endorphins have many nitrogen atoms , doesn`t exist a reuptake pump ?! Also why only by monoamine cand exista a reuptake pump, and to endo not. Also doesn`t exist presynaptic receptors which give endorphines to postsynaptic receptors ?! Something (presynaptic receptors) must give endorphins to opioid receptors (I think postsynaptic receptors). And when presynaptic and postsynaptic receptors exist, also a reuptake pump exists too. And we can make a ERI medication.
Why does it matter that they are not monoamines ?! poli or mono, normal must be same mechanism.

Why would it be the same mechanism? Endorphins are a form of neurotransmitter called neuropeptides which means they resemble small proteins in structure. Look at this picture and you can see how much bigger a neuropeptide is vs. a small molecule neurotransmitter like a monoamine. Even just for that reason alone you can see how much harder it would be transport them back to the presynaptic cell.

 

[Ovideo_1978]

Yes, but the human mind must find a method (to eat is too hard sometimes...) to put back endorsphins in the presynaptic receptors, because can help in rezistent depression ! Is much better to use internal endorphine than external, wich are not 100 % same, and the stimulation of postsynaptic receptors are not 100 % same, the brain says "hmm this is not my endorphine". like to Insulin, you get external Insulin, but the internal are much better managed by the body, more glucose stability and more. The effect of internal endorphine, insulin and others, are much accurate ! You cand say that agonits are same like internal endorpshines, but realy can not be so.

I felt that the agonists and partial agonists gave me a little different effect than the internal, when the internal endo were ok in the past ! In the past I felt allways okey, much more stable, with agonists, i was better for a few hours or maximal 20 hours with Suboxone, but after that I felt sometimes even worse than I felt before Suboxone, even if before Suboxone i felt too not so good, after subo was worse, I must take again, after a 2-3 weeks, the effect was shorter, and i felt more bad after the effect was gone.
Also...? And was not a large dose ! My doc said oral 0,25 or maximal 0,5 mg Subo/day, or oxycontin maximal 2,5 Mg/day. He said that to this very low doses tolerance and dependence doesn`t appear. But I observed that tolerance appeared, and dependence too (because i felt worse after the effect was gone).
With internal endo I felt so ? NO !! All was okey allways, no tolerance, nothing.
Why was happening so ?! Why with subo or oxy was not like when internal endo worked okey ?!

And I think that a ERI cand better help like agonists or partial agonists, because we work with natural internal endo. I think, but I am not sure, because that I'm consulting with you all, to learn some thing and more, find a solution.

 

[thegreenhand]

You didn’t have tolerance to endorphins because your body knows how much to release. If it dumped it all at once then yes there would be a tolerance. If you go on a run and feel the endorphins after and then immediately go on another run you won’t feel the power of the endorphins as much.

Quite frankly, your idea is not possible. Small neurotransmitters have reuptake proteins that act like a machine to take it back in. No such proteins exist for endorphins, rather they have proteins that break down them and recycle the endorphins into another use. It’s not possible because our bodies lack the machinery

 

[Ovideo_1978]

Yes, and with agonists we can`t calculate dosage so 90 % like natural stimualtion ? Can`t be not perfect but in some procent. Because doesn`t mather how is the dosage, is fack ! All goses bad. This is the probleme which I don`t understand. Like insulin, we make it as close to nature as possible. And from where knows the organism exactly how much must give ?! To insulin is simple, es dependig from glucose level, the dose of insulin for droping glucoze to normal levels, but to endorphins ?! Because endo don't need to adjust something !