64 replies to this topic

[Rorororo]

Anyone know of a natural MU opioid agonist that can be combined with:

 

purple prairie clover & lotus flower?

 

 

It can be weak.  

 

I would suggest black black cohosh but it looks like its an SSRI on the 5-ht-7 receptors....If there is something else then that would be awesome.  I am sure a low dose won't be too bad.... If it's avoidable then it will be preferred.

 

 

BTW the reviews on Lotus aligns with a KOR antagonist!  (relief from depression and anxiety....they also state pain relief since its also a mu and delta agonist) 

Edited by Rorororo, 24 May 2020 - 12:51 AM.

[Rorororo]

Looks like Dalea purpurea is hydrophobic, it wont dissolve in water.   I *believe* ethanol will do the trick.  So put your flowers in a jar (weigh them first) full of a high percentage alcohol.  Once I find my mu opioid agonist, I will write out a guide for this.  I hope it will help others.

Edited by Rorororo, 24 May 2020 - 04:17 AM.

[Rorororo]

Looks like Dalea purpurea is hydrophobic, it wont dissolve in water.   I *believe* ethanol will do the trick.  So put your flowers in a jar (weigh them first) full of a high percentage alcohol.  Once I find my mu opioid agonist, I will write out a guide for this.  I hope it will help others.

 

 

 

 

https://sci-hub.tw/10.1021/np030258d

 

So, they used whole plants....The active ingredient is *most* likely in the flower (wild guess).  They used 234 grams of the whole plant (if I read it correctly).  A really sketchy way of doing this is taking chaste berry, then take some extract.  Once you see you the libido effects wear off from the chaste berry then stop..you will have a good guesstimate on how much antagonism you now have.... Obviously, start with one flower under the assumption that the dosage will be 39mg

 

 

I am also open to suggestions (even official testing) to verify the dosage.  I mean, if one flower head (average size) has 39 mg of Pawhuska A then you have a rough estimate.   This is totally under the assumption that Pawhuska A lies in the pink leaves.  I want to do some reading and see.  I *doubt* its in the other green material (the stem and the large green head). 

Edited by Rorororo, 24 May 2020 - 06:21 AM.

[Rorororo]

Looks like lotus has toxic materials?  Sketchy....

 

https://www.research...ss_spectrometry

 

 

Also, for quercetin...I believe I was correct. 

 

https://pubs.acs.org....1021/np070194x

 

I thought I read it inhibited KOR at 51% (lotus flower)....I might have read it incorrectly....

 

 

I think purple Prairie Clover + chaste tree is a simpler and maybe even safer (toxicity report) route to take. 

Edited by Rorororo, 24 May 2020 - 06:43 AM.

[Rorororo]

Looks like lotus has toxic materials?  Sketchy....

 

https://www.research...ss_spectrometry

 

 

Also, for quercetin...I believe I was correct. 

 

https://pubs.acs.org....1021/np070194x

 

I thought I read it inhibited KOR at 51% (lotus flower)....I might have read it incorrectly....

 

 

I think purple Prairie Clover + chaste tree is a simpler and maybe even safer (toxicity report) route to take. 

 

I found a *possible* selective mu agonist (under the assumption that the lotus is not toxic):

 

https://doi.org/10.1...1472-6882-14-63

 

 

I would also make sure that the lotus flower does inhibit KOR.  It was late last night but I think I might have read contradicting information.  

[StevesPetMacaque]

Intranasal nor-binaltorphimine at about 0.3 mg / day worked surprisingly well in my experience. It's a bit dysphoric due to short term mu and kappa antagonism, but the long term effects included noticeable improvements in executive function / attention / problem solving. At this dose, I'm unconcerned about the irregular heart rhythm that was occasionally reported with the oral route.

 

I wish JDTic were still around - it was a lot easier to get one's hands on and worked about the same, from what I've heard.

[Rorororo]

Intranasal nor-binaltorphimine at about 0.3 mg / day worked surprisingly well in my experience. It's a bit dysphoric due to short term mu and kappa antagonism, but the long term effects included noticeable improvements in executive function / attention / problem solving. At this dose, I'm unconcerned about the irregular heart rhythm that was occasionally reported with the oral route.

 

I wish JDTic were still around - it was a lot easier to get one's hands on and worked about the same, from what I've heard.

 

 

You can pair with a mu agonist like the one I posted above.  Also, do you have a source for Norbinaltorphimine?  I rather stick to a herbal remedy but still...

Edited by Rorororo, 25 May 2020 - 12:44 AM.

[Rorororo]

This *might* inhibit KOR 

 

https://www.research..._new_flavonoids

 

 

its from the same family of plant (buckwheat) that I posted earlier, that is a JNK activator.  

 

KOR activates GIRK channels btw.

 

There is direct literature for it but inhibiting GIRK might be the route you want to take (look at the first couple of posts).  I would give it a shot if I were you, its a whole lot cheaper than Norbinaltorphimine.  If you notice the same benefits, might as well keep using it

 

A really shotgun approach would be dextromethorphan, I believe that inhibits the same GIRK channels...but it does a whole lot of stuff too....

 

 

Message me for a source. 

 

I need to read it, but if it is in vivo then the mechanism might a KOR antagonist. 

Edited by Rorororo, 25 May 2020 - 01:04 AM.

[Rorororo]

Also looks like methylcoclaurine is responsible for kor antagonist properties in the lotus. IF it is not toxic, maybe look for a plant that is comprised of that without any mu activities  You will have your KOR antagonist plant 

 

I am unsure if it is only selective at KOR...it will take further reading

 

 

WAIT....not according to this: https://www.ncbi.nlm...les/PMC4636954/

 

 

Getting purple Prairie Clover and chaste tree is much easier. 

Edited by Rorororo, 25 May 2020 - 02:46 AM.

[Rorororo]

According to: https://www.scienced...074774215000446

 

 

 

3.4 Opioids

GIRK channels are coupled to μ-, κ-, and δ-opioid receptors (Nagi & Pineyro, 2014), and as discussed earlier, animal and human studies provide corroborating evidence that GIRK channels mediate opioid analgesia (Tables 2 and 3). In addition, GIRK signaling is important for the motor-stimulating effects of morphine. GIRK2/3 channels in VTA dopamine neurons were required for the motor-stimulatory effect of systemic morphine, whereas GIRK1/2 channels in VTA GABA neurons were not involved (Kotecki et al., 2015). Thus, GIRK channels appear to regulate opioid-induced motor activity in a cell- and subunit-dependent manner. This work illustrates the utility of selective ablation of GIRK subunits in individual neurons to decipher cellular- and subunit-specific GIRK signaling. GIRK2/3 channels in VTA dopamine neurons are also important in mediating the motor-stimulatory effects of cocaine (Munoz & Slesinger, 2014) and may be a common target for other drugs of abuse (Cruz et al., 2004; Herman et al., 2015; Labouebe et al., 2007).

GIRK channels are also implicated in dependence after chronic exposure to morphine (Tables 2 and 3). For example, morphine withdrawal symptoms were greatly reduced in mice lacking Girk2/3−/− (Cruz et al., 2008). Electrophysiological responses in brain slices from these mice lacked the increased spontaneous firing that is associated with morphine withdrawal, and postsynaptic GIRK currents were abolished. In humans, an SNP in KCNJ6 (GIRK2) was associated with increased opioid requirements for analgesia and a lack of opioid withdrawal symptoms (Lotsch et al., 2010).

Interestingly, tolerance to repeated morphine administration may be associated with increased potency and sensitization of opioid receptors. Opioids have a biphasic effect on GIRK currents from periaqueductal gray neurons (which contribute to opioid antinociception and tolerance) in morphine-tolerant rats (Ingram, Macey, Fossum, & Morgan, 2008). GIRK currents were initially potentiated by met-enkephalin and inhibited by a μ-opioid antagonist in brain slices from morphine-pretreated rats, suggesting that repeated morphine exposure in vivo enhances agonist stimulation of μ-opioid receptors; however, peak GIRK currents in slices from morphine-tolerant rats exhibited greater desensitization. The altered μ-opioid–GIRK signaling may contribute to the development of opioid tolerance.

 

 

If it is coupled....wouldn't inhibiting one bring the other down?  

Edited by Rorororo, 25 May 2020 - 03:57 AM.

[Rorororo]

I must say, trying to downregulate Kappa Opioid receptors by agonism is a really bad idea. It is mentioned here or there that opioid receptors actually don't regulate inversely, but they upregulate by agonism and downregulate by antagonism, at least in most cases (there seem to be paradoxes in some opioid reactions). One can try this oneself by taking menthol, which is absolutely sufficient in concentrated form as an agonist, and look whether high doses of it ever yield a better result - or any other result from its acute action - than one evening's high dose of chamomille (with apigenin) which in turn is completely sufficient for antagonism.

 

He *might* be right:

 

 

 

In a study examining post-mortem tissues from 14 alcoholics versus 14 healthy controls, increased Pdyn mRNA and dynorphin peptides A and B were observed in the dorsolateral PFC, as well as increased KOR mRNA in the orbito-frontal cortex, whereas, no change was found for other opioid peptides and receptors (120) in these regions.

 

reference: http://eutils.ncbi.n...ref&id=21955155

 

Alcohol is *probably* a k-opioid agonist

 

https://medicalxpres...ne-effects.html

 

an antagonist stopped the urge of consuming more alcohol, you can *jump to the conclusion* it  *might* be an agonist.  It is lowering tolerance and the urge to drink more. 

 

If he is right, then it should have DECREASED KOR mRNA, right?  

 

 

THEN....

 

https://www.longecit...eriance-report/

 

his effects remained until they subsided after a month. If Davex is incorrect then wouldn't he be worse off then he was before jdtic administration?  

 

I believe he, DaveX, is correct here. 

 

 

 

Also, according to:

https://www.ncbi.nlm...les/PMC4636954/

 

The best way to do this with herbs is getting purple prairie clover, make it to a tincture (with high proof alcohol) then get WHITE sacred lotus flowers that are dried then grind them up to a powder then take the capsules, it should be 30 mg/kg with the rats(?) or mice they used then convert it back to human doses.  This way you get a KOR inhibitor + MOR and DOR agonists with the lotus then a KOR antagonist + MOR and DOR antagonists with the purple prairie clover. 

 

Whats bother some so far:

 

The dosage of the purple prairie flower

Ensuring that the lotus is not toxic and actually a KOR inhibitor

Edited by Rorororo, 26 May 2020 - 12:19 AM.

[Rorororo]

This might be useful (for the purple prairie clover extraction):

 

 

https://sci-hub.tw/1...lecules23030586

[Rorororo]

This is interesting:

https://pubmed.ncbi....h.gov/10999950/

 

Correct me if I am wrong but a KOR antagonist and GIRK inhibitor can work synergistically to downregulate KOR? If so, awesome!

 

I am also curious if the KOR agonist caused UP regulation. They stated it did NOT do down regulation in mice.  They could have chosen to omit the up-regulation part LOL

 

 

Sooo.....

 

Wouldn't a stack of:

 

 

Forskolin

Butea Superba

Quercertin 

Purple Prairie Clover

White Sacred Lotus

Girk inhibitor (you have options) 

 

Be the ultimate stack to down-regulate KOR?   It is a natural and relatively safe stack too.  That is, if you find a natural Girk inhibitor.

 

 

I actually found two natural girk inhibitors

polygonum persicaria:

https://pdfs.semanti...15399be01f1.pdf

Brick cap mushrooms:

https://www.scienced...367326X19310627

 

 

Possibly 3:

https://www.research...Blocking_Effect

 

 

 

Caveats:

 

polygonum persicaria: exhibited high GIRK activity WITH a chloroform extract not a water extract.  Can anyone explain the discrepancies of this and will it be applicable in vivo?  As in, can some take polygonum persicaria and inhibit GIRK w/o using chloroform as a solvent? I would think so? 

 

Brick cap mushrooms: Had hERG activity (heart activity)... I would stay away

 

White Sacred Lotus: Does it it inhibit KOR?  Also, what else does it do.... Might want to replace with a higher concentration of purple prairie clover and chaste tree if it does other unwanted stuff.

Edited by Rorororo, 02 June 2020 - 07:57 AM.

[Rorororo]

This is interesting:

https://pubmed.ncbi....h.gov/10999950/

 

Correct me if I am wrong but a KOR antagonist and GIRK inhibitor can work synergistically to downregulate KOR? If so, awesome!

 

I am also curious if the KOR agonist caused UP regulation. They stated it did NOT do down regulation in mice.  They could have chosen to omit the up-regulation part LOL

 

 

Sooo.....

 

Wouldn't a stack of:

 

 

Be the ultimate stack to down-regulate KOR?   It is a natural and relatively safe stack too.  That is, if you find a natural Girk inhibitor.

 

 

I actually found two natural girk inhibitors

polygonum persicaria:

https://pdfs.semanti...15399be01f1.pdf

Brick cap mushrooms:

https://www.scienced...367326X19310627

 

 

Possibly 3:

https://www.research...Blocking_Effect

 

 

 

Caveats:

 

polygonum persicaria: exhibited high GIRK activity WITH a chloroform extract not a water extract.  Can anyone explain the discrepancies of this and will it be applicable in vivo?  As in, can some take polygonum persicaria and inhibit GIRK w/o using chloroform as a solvent? I would think so? 

 

Brick cap mushrooms: Had hERG activity (heart activity)... I would stay away

 

White Sacred Lotus: Does it it inhibit KOR?  Also, what else does it do.... Might want to replace with a higher concentration of purple prairie clover and chaste tree if it does other unwanted stuff.

 

Looks the plants minor continents inhibited GIRK which explains the chloroform difference.  Looks like the minor continents were soluble in chloroform while the others were not. 

[jacobjerondin]

Hmmm you may be right that agonists are not the best approach, altho I have read all the reports on Salvia that I can find and it seems that a subset of people do report sustained benefits (which implies KOR downregulation following the initially dysphoric trip) from microdosing/low dosing the plain leaf, either by smoking it or by quidding it.

 

The pharmacology with this receptor seems to be complex, and it greatly oversimplifying things to say that KOR agonists do not downregulate the receptor and/or KOR antagonists do not upregulate it. The long term receptor changes have something to do with the G biased protein activity that I don't currently fully understand.

 

Anyway, I really appreciate all the research and info you've been sharing but I am worried about the cardiac arrhythmia issues that JDtic was associated with, which might be mediated by JNK activation. See here, for example: https://www.nature.c...icles/npp201527. 

 

 

 

Kappa-active compounds also have cardiovascular effects; however, results are mixed. In most rat studies, kappa opioid receptor agonists (KORAg) are cardioprotective (eg, Jaiswal et al, 2010; Zhou et al, 2001), reduce arrhythmias (eg, Jin-Cheng et al, 2008; Lishmanov et al, 2007; Peart et al, 2004; Xiu et al, 2013), have positive inotropic effects (eg, Pyle et al., 2001), and are a component of ischemic preconditioning (Yu et al, 1999; Zatta et al, 2008). Consequently, KORAn could have negative effects. One study reported that highly selective KORAn activate c-Jun N-terminal kinase (JNK; Bruchas et al, 2007). In another study, lipopolysaccharide activation of JNK caused disruption of fatty acid oxidation by a human ventricular-derived cardiomyocyte cell line and caused cardiac dysfunction in C57BL/6 mice (Drosatos et al, 2011). However, in dogs (Hartlage et al, 2006) and swine (Coles et al, 2003), KORAn are cardioprotective. Also, negative inotropic (Ventura et al, 1992) and pro-arrhythmic (Bian et al, 1998) effects of U-50,488H and cardioprotective effects of nor-BNI (Liu et al, 2005) are described in rats.

 

I think you are onto something very promising and potentially even revolutionary here but we need to better establish the safety of JNK activation first. I agree that intranasal use may bypass some of the issues with the oral ROA but that might be hard to do with the purple prairie extract. By the way, sacred white lotus is fairly popular entheogen and is very safe, you just need to make sure you get a good strong extract of it and don't get blue lily/lotus which it's often confused with.

Edited by jacobjerondin, 05 June 2020 - 11:43 PM.

[StevesPetMacaque]

JNK is one of those general oxidative stress pathways, IIRC, which is why its effects are really hard to pin down in isolation. Oxidative stress can drive hormetic responses but also inflammatory ones. Here, check this out. JNK off, aerobic capacity goes up; JNK on, muscle anabolism does. Aside from reducing cardiovascular activity and not megadosing antioxidants while taking KOR antagonists, I don't think it's fruitful to focus on the JNK part of the equation.

[Rorororo]

JNK is one of those general oxidative stress pathways, IIRC, which is why its effects are really hard to pin down in isolation. Oxidative stress can drive hormetic responses but also inflammatory ones. Here, check this out. JNK off, aerobic capacity goes up; JNK on, muscle anabolism does. Aside from reducing cardiovascular activity and not megadosing antioxidants while taking KOR antagonists, I don't think it's fruitful to focus on the JNK part of the equation.

 

 

Quercertin is also know for its cardiovascular protective effects. 

 

You can also follow the pathways that one article stated that KOR was downregulated and try to attacks those.  

 

Or, you can also take out purple prairie clover and white lotus if one has concerns with their heart.  

 

 

I am honestly so tired with this topic.  I swear there is so many contradicting information (like JNK activators) and a little information on this. Its definitely hard to attack. I just wish more focus was produced on it from the pharmaceutical industry.  

 

Sure, micro-dosing this regimen, while attacking different pathways *might* work, theoretically.  The dosage is sketchy (purple prairie clover) and no anecdotal reviews out there.  You can make rough guesses but its just sketch not knowing exactly the dosages. 

 

 

Also, I don't think KOR down-regulates with agonists.  I would assume opioid users have more anhedonia than prior.  There could be a lot of variables though.  

Edited by Rorororo, 06 June 2020 - 12:37 AM.

[DaveX]

He *might* be right:

 

How "nice", you spamming little troll. I had only seen that other request for "sources" well after my original post, but at that point I wasn't necessarily acquainted with all the particular sources anymore or much concerned with that topic.

 

Nonetheless, that downregulation and upregulation of K opioid receptors occurs in the reverse of most talked-about receptors (antagonism downregulates, agonism upregulates) is one of the most basic things one can't miss if one seriously concerns oneself with any of the research, implicit to any of the studies, sometimes explicit.

(It is for example explicit in how one of the main prescription drugs for downregulation is a pure antagonist. This can only be explained with additional assumptions to the premise or a "paradoxical" reaction, but at least it should make one pay attention to it. However I have only found sudies of K-antagonism and agonism that work like this, not making it paradoxical.)

 

I also mentioned an easy way to test (even in the preferred opposite way...) and my statement wasn't that controversial, except that it contradicted the blind assumption of the thread starter.

Edited by DaveX, 07 June 2020 - 09:07 PM.

[Rorororo]

How "nice", you spamming little troll. I had only seen that other request for "sources" well after my original post, but at that point I wasn't necessarily acquainted with all the particular sources anymore or much concerned with that topic.

 

Nonetheless, that downregulation and upregulation of K opioid receptors occurs in the reverse of most talked-about receptors (antagonism downregulates, agonism upregulates) is one of the most basic things one can't miss if one seriously concerns oneself with any of the research, implicit to any of the studies, sometimes explicit.

(It is for example explicit in how one of the main prescription drugs for downregulation is a pure antagonist. This can only be explained with additional assumptions to the premise or a "paradoxical" reaction, but at least it should make one pay attention to it. However I have only found sudies of K-antagonism and agonism that work like this, not making it paradoxical.)

 

I also mentioned an easy way to test (even in the preferred opposite way...) and my statement wasn't that controversial, except that it contradicted the blind assumption of the thread starter.

 

 

I said that because I do not know. 

 

 

That being said one has to look at these pathways:

 

 

 

These results indicate that U50,488H-induced down-regulation of the hkor involves GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms and receptors seem to be trafficked to lysosomes and proteasomes for degradation. Thus, U50,488H-induced internalization and down-regulation of the hkor share initial common mechanisms.

 

From: https://pubmed.ncbi....h.gov/10999950/

 

 

I believe GIRK inhibition (GRK) will help.  Looks like SSRI might help and maybe others with (arrestin-2).  I do not know anything about (dynamin-, rab5-, and rab7-) I also have to reread the literature about cAmp and see if it plays here or if it is another mechanism. What I am confident that will downregulate it is....

 

 

 

Quercetin (KOR and MOR antagonist; more selective at KOR; also increase in NO)

Increase in test. 

cAmp increase (from OP)

*maybe* girk inhibition

 

 

I am a little iffy on GIRK inhibition; if someone can chime more in this.  If someone wants to hop in and help....maybe look into (arrestin-2) that doesnt involve serotonin and  (dynamin-, rab5-, and rab7-) 

 

 

I am not sure if those pathways need to either be upregulated or downregulated

 

but curcumin *might* help with rab7:

https://www.tandfonl...4161/auto.19471

 

 

I am *guessing* upregulated from this basis:

Rab5 and Rab7 Control Endocytic Sorting along the Axonal Retrograde Transport Pathway

https://www.cell.com...6273(06)00640-4

 

JDTic May Restore Axonal Damage

https://www.longecit...-axonal-damage/

 

 

I just read the titles as I am a little tied up but this takes a lot of work to look into to know with confidence (which I cant say with this topic).  If anyone wants to help, then here you go. 

 

Unless I am totally mixing it incorrectly:

 

 

A combination of chloroquine and proteasome inhibitor I abolished U50,488H-induced down-regulation.

 

From that same article.  I believe chloroquine acts the same as a GIRK inhibitor....

 

so it looks like you want a proteasome inhibitor I...which might get you want you want...downregulated KOR...coupled with girk inhibiton, cAmp increase, test and NO

 

 

 

EDIT: 

From

https://en.wikipedia...asome_inhibitor

 

I see EGCG could be a proteasome inhibitor also found Tomatine from tomatoes to be one (this might be useful:http://www.sciencema...d.php?tid=76570)

 

However, looks like EGCG might me a JNK inhibitor. So maybe double down on JNK activation?

 

So...maybe the best best is...

 

Quercetin (KOR antagonist; JNK activator and increase NO)

Forskolin and Butea Superba (increase in cAmp and Test)

EGCG (proteasome inhibitor)

Girk inhibitor - (you can make your own with that plant, choloform and basic chem knowledge or buy a synthetic one)

Perhaps double dose of quercetin from EGCG or another jnk activator?

 

I also found this:

https://pubmed.ncbi....h.gov/17958328/

 

I would just micro dose that stack and add l citrulline when it makes sense (at night...long after Quercetin) 

 

I also think chloroquine is a analogue from a natural source and you can get it from Quinine this will be in lieu of the girk inhibitor. 

Edited by Rorororo, 07 June 2020 - 10:34 PM.

[Rorororo]

It makes sense why EGCG is in here alongside quercetin

 

https://www.ncbi.nlm...les/PMC2265593/

 

I wouldn't worry too much about the *possible* jnk inhibition by EGCG.  There is so many contradicting studies on this topic.  

 

 

I guess I found the stack I have been trying to create!

 

You can always make it stronger\quicker (i wouldn't) with more potent substances....this is going to take more work and more risky ={

Edited by Rorororo, 07 June 2020 - 11:10 PM.

[Rorororo]

Heres a good reference for Natural Compounds with Proteasome Inhibitory Activity

 

https://www.ncbi.nlm...les/PMC3303152/

[nickthird]

Report:

 

Forskohlii: no effect.

Quercetin and bromelain (get from Amazon): works but the duration is maybe 30 minutes.

[Rorororo]

Report:

 

Forskohlii: no effect.

Quercetin and bromelain (get from Amazon): works but the duration is maybe 30 minutes.

 

You need to pair the forskohilli with a PDEi (this is how CILTEP works btw) like butea superba (this will raise test. so I will recommend) or luteolin. Sorry, I should have specified this. 

Report:

 

Forskohlii: no effect.

Quercetin and bromelain (get from Amazon): works but the duration is maybe 30 minutes.

 

 

Try a stack of:

 

Quercetin (KOR antagonist; JNK activator and increase NO)

Forskolin and Butea Superba (increase in cAmp and Test)

EGCG (proteasome inhibitor)

Girk inhibitor - (you can make your own with that plant, choloform and basic chem knowledge or buy a synthetic one)

 

 

This works by the same pathways proven to downregulate KOR as reported in the article I linked prior. 

Edited by Rorororo, 12 June 2020 - 03:28 AM.

[nickthird]

Have you tried this and has it worked for you?

[Rorororo]

Have you tried this and has it worked for you?

 

No, I haven't tried it. I am also planning on revisiting it sometime soon and do a little more research.  I am kind of tired of the topic to be honest.  I was hoping someone can hop in and take over.

[Rorororo]

No, I haven't tried it. I am also planning on revisiting it sometime soon and do a little more research.  I am kind of tired of the topic to be honest.  I was hoping someone can hop in and take over.

 

 

I believe I misread the study.

 

Looks like you want to focus on these pathways:

 

 

 

Coexpression of GRK2 or GRK2 and arrestin-2 permitted etorphine to induce down-regulation of the hkor, although expression of arrestin-2 or dynamin I alone did not.

 

 

proteasome helped degrade k-opioid receptors.... 

 

My logic *at first* was if it blocks a kor agonist it could be acting as an antagonist.  

 

The study is saying expression of girk helped induce down regulation. However, keep in mind this is from hamsters. They did not observe this with mice. Who know if it will apply to mice?  I suggest inhibiting GIRK.  

 

Here is the study:

https://sci-hub.tw/h...24/mol.58.4.795

 

 

I have some bro science logic I want to share....if you antagonize KOR and stop its degradation of the receptors (with EGCG) your brain wouldn't produce new receptors and you will just lower the threshold of KOR.   I haven't read the study fully but one day, I plan to.  Also read more studies on this.  

 

There is also this from the study:

 

Effects of Expression of the Dominant Negative Mutants Arrestin-2(319-418) and Dynamin I-K44A on (2)U50,488H Induced Down-Regulation of the Human k-Opioid Receptor. Expression of arrestin-2(319-418), a dominant negative mutant that inhibits receptor internalization by binding constitutively to clathrin (Krupnick et al., 1997), effectively reduced U50,488H-induced down-regulation (Fig. 2). Dynamin I-K44A, a dominant negative mutant that blocks endocytosis at a stage preceding the sequestration into deeply invaginated coated pits (van der Bliek et al., 1993), significantly attenuated (2)U50,488H induced downregulation of the human k-opioid receptor (Fig. 2). Neither arrestin-2(319-418) nor dynamin I-K44A affected the expression level of the receptor. The results indicate that downregulation of the human k-opioid receptor occurs via arrestin-2- and dynamin I-dependent mechanisms

 

&

 

Effect of Expression of GRK2, Arrestin-2, and Dynamin on Etorphine-Induced Down-Regulation of the Human k-Opioid Receptor. Expression of GRK2 plus arrestin-2 or GRK2 promoted etorphine-induced down-regulation of the human k-opioid receptor, whereas expression of dynamin I alone did not (Fig. 3). Arrestin-2 alone seemed to have a modest effect in promoting etorphine-induced downregulation, but the effect did not reach statistical significance (Fig. 3). GRK2, arrestin-2, dynamin I, or GRK2 plus arrestin-2 did not affect the expression level of the human k-opioid receptor in CHO-hkor cells. We reported previously that over-expression of the dominant negative mutant GRK2- K220R, arrestin-2(319-418), or dynamin I-K44A significantly inhibited U50,488H-induced internalization of the human k-opioid receptor expressed in CHO cells, indicating that (2)U50,488H-induced internalization of the human k-opioid receptor occurred via GRK-, arrestin-2- or dynamin I-dependent pathways (Li et al., 1999). These results further support

 

chrysin & Resveratrol decreases arrestin-2 ... possibly quercetin does too?  I would focus my attention on chrysin to see if it fits well here. 

 

Honestly, I skimmed the article. I would also read it and comprehend the mechanisms behind down regulation. 

 

 

Quercetin (KOR antagonist; JNK activator and increase NO)

Forskolin and Butea Superba (increase in cAmp and Test)

EGCG (proteasome inhibitor)

Girk inhibitor - (you can make your own with that plant, choloform and basic chem knowledge or buy a synthetic one)

chrysin - Decreases arresrin-2 and increase Test & N.O. 

 

Edited by Rorororo, 13 June 2020 - 07:40 PM.

[Rorororo]

I would also find a safe and natural lysosome inhibitor other than quinine.  

 

Edit:

 

Looks like sacred lotus seeds can inhibit lysosome the same way as chloroquine

 

 

 

 

Sources:

(sacred lotus seeds): https://pubmed.ncbi....h.gov/26114658/

 

 

(Chloroquine MoA of lysosome inhibition) https://www.tandfonl...27.2018.1474314

 

 

You can also buy the extract online.  There one article that states that sacred lotus is a KOR inhibitor too!

 

 

Quercetin (KOR antagonist; JNK activator and increase NO)

Forskolin and Butea Superba (increase in cAmp and Test)

EGCG (proteasome inhibitor)

Girk inhibitor - (you can make your own with that plant, choloform and basic chem knowledge or buy a synthetic one)

chrysin - Decreases arresrin-2 and increase Test & N.O. 

Sacred lotus seed extract - Probable KOR inhibitor (sacred lotus flowers are KOR inhibitors) and lysosome inhibitor 

 

Edited by Rorororo, 13 June 2020 - 10:34 PM.

[Rorororo]

Interesting:

 

 

 

Data analysis revealed that morphine decreased MOP and NOP receptor gene expression, whereas naloxone elicited their up-regulation. In addition, pre-treatment with naloxone prevented the morphine-elicited gene expression alterations. Interestingly, WSE was able to: a) alter MOP but not NOP gene expression; b) counteract, at its highest concentration, morphine-induced MOP down-regulation, and c) hamper naloxone-induced MOP and NOP up-regulation

 

From: https://www.ncbi.nlm...les/PMC5761194/

 

Looks like you want to induce Autophagy not reduce it.  Which makes sense why ibogaine is widely used for opioid addiction.. 

 

So looks like you want to inhibit these pathways:

 

 

 

GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms

 

Which you can do by:

 

 

Girk inhibitor: Synthetic or that chloroform extract of that plant - GRK

chrysin - Decreases arresrin-2 and increase Test & N.O.  - arrestin-2

Melotonin and Vit. D - dynamin
Methionine, DHA, choline - rab5
?- rab7

 

Upregulate these:

 

 

receptors seem to be trafficked to lysosomes and proteasomes for degradation

 

 

Which can be done with GDNF boosting substances (guess)

 

 

Ashwagandha - From: https://www.ncbi.nlm...les/PMC5761194/

 

lysosomes modulator - 
proteasomes modulator - 

 

Then here is luteolin (another GDNF promoter):

https://europepmc.or.../pmc/pmc6192304

 

I would research luteolin further and see if you can combine it with Ashwagandha (different mechanism of induced GDNF) 

I know Naringin is one but I believe it activates GIRK so it might be counter-productive to use. 

 

Then you can antagonize KOR hoping for further downregulation by:

 

Quercetin (KOR antagonist; JNK activator and increase NO) - See many posts about JNK activators above

Forskolin and Butea Superba (increase in cAmp and Test) - See first posts

 

Edited by Rorororo, 14 June 2020 - 10:58 PM.

[Rorororo]

I would take out the quercetin https://www.ncbi.nlm...pubmed/14499317

 

Another contradicting article. I would rather play it safe.

[Rorororo]

Ashwagnhda increases lysosome

Royal Jelly increases proteasome

 

 

I believe mTor can inhibit rab5 and rab7 so intranasal insulin should increase mTor and therefore inhibit rab5 and rab7

 

So looks like you want to inhibit these pathways:

 

GRK-, arrestin-2-, dynamin-, rab5-, and rab7-dependent mechanisms

 

 

 

 

 

Which you can do by:

 

 

Girk inhibitor: Synthetic or that chloroform extract of that plant - GRK

chrysin - Decreases arresrin-2 and increase Test & N.O.  - arrestin-2

Melotonin and Vit. D - dynamin
intranasal insulin, DHA, choline - rab5
intranasal insulin - rab7

Upregulate these:

 

 

receptors seem to be trafficked to lysosomes and proteasomes for degradation

 

 

Which can be done with GDNF boosting substances (guess)

 

Ashwagandha - From: https://www.ncbi.nlm...les/PMC5761194/

 

lysosomes modulator - Ashwagandha 
proteasomes modulator - Royal Jelly

Edited by Rorororo, 15 June 2020 - 01:10 AM.