How Well Do You Know The Kappa Opioid System?

[Lokzo]

I find this aspect of the opioid network highly interesting:

-1Opioid Receptors
Kappa opioid receptors are located on dopamine axon terminals (Svingos et al., 2001).

-The κ-opioid receptor binds to the endogenous ligand, dynorphin, and acts to decrease dopamine release.151

The dynorphin/kappa opioid receptor (KOR) system is implicated in the “dark side” of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters;

Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing.

Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function.


KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals.

Feel free to leave a comment below on what you have discovered:

 

[morgan#1]

I’ve discovered I am a dullard. Makes me feel stuuupid! Following, cause I want to see if I get smarter. Fascinating.

 

[Terma]

Yeah, well the thing I don't have a great grasp on is exactly how the KOR receptors sensitize/traffic (not always straightforward, at least I don't assume), and some of the fear extinguishing effects of KOR agonism aren't clear. Plus, like oxytocin and others I think its interpretation must be complicated by systemic administration of test compounds, which hit all the brain areas. Dynorphin is also at least partly response for the analgesic effects of some cannabinoids (some study or two even claimed it was entirely responsible, iirc). There is also propranolol as noted in haidut's thread and I wonder where it intersects with KOR besides its dopamine-killing power you'd expect to lower (nor)epinephrine (there is also a role for GABAA in fear extinction, and other things). In other words, I'm 99% sure this system is involved in my experiences and issues, but I can't quite tell you how.

It certainly kills off dopamine but also serotonin release:
Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Although stress has profound effects on motivated behavior, the underlying mechanisms responsible are incompletely understood. In this study we elucidate a functional pathway in mouse brain that encodes the aversive effects of stress and mediates stress-induced reinstatement of cocaine place preference (CPP). Activation of the dynorphin/kappa opioid receptor (KOR) system by either repeated stress or agonist produces conditioned place aversion (CPA). Because KOR inhibition of dopamine release in the mesolimbic pathway has been proposed to mediate the dysphoria underlying this response, we tested dopamine-deficient mice in this study and found that KOR agonist in these mice still produced CPA. However, inactivation of serotonergic KORs by injection of the KOR antagonist norBNI into the dorsal raphe nucleus (DRN), blocked aversive responses to the KOR agonist U50,488 and blocked stress-induced reinstatement of CPP. KOR knockout (KO) mice did not develop CPA to U50,488; however, lentiviral re-expression of KOR in the DRN of KOR KO mice restored place aversion. In contrast, lentiviral expression in DRN of a mutated form of KOR that fails to activate p38 MAPK required for KOR- dependent aversion, did not restore place aversion. DRN serotonergic neurons project broadly throughout the brain, but the inactivation of KOR in the nucleus accumbens (NAc) coupled with viral re-expression in the DRN of KOR KO mice demonstrated that aversion was encoded by a DRN to NAc projection. These results suggest that the adverse effects of stress may converge on the serotonergic system and offers an approach to controlling stress-induced dysphoria and relapse.

Since it plays the part of a "failure" signal - it seems - it would be logical for it to get rid [or limit] serotonin because brain serotonin is "predictive" in function, so they seem made for different moments during a challenge. Another way to look at it is that serotonin is involved in implementing "patience" toward stressors, and you would want to lose that at the end. Cortisol also does acutely as was posted. I still have a lot more to read about this system, but experiments with fear memory are difficult to follow. Also time. This must be the first dedicated thread to this on here (?).

Edit: Forgot about this one where it actually downregulated SERT instead:
Modulation of Serotonin 1Transporter Function by kappa-Opioid Receptor Ligands

Since acute KOR activation decreases 5-HT release, reduction in synaptic 5-HT could reduce SERT surface expression, as our prior report has shown that SERT activity (5-HT transport) can antagonize downregulation of SERT (Ramamoorthy and Blakely, 1999). Moreover, it is also possible that decreased synaptic 5-HT might also modify 5HT1B-mediated SERT regulation (Daws et al., 2000).

I think there is some dynamic based on the brain area and length of exposure or such, because there's a point where you expect it to "register" with the serotonin system. I'm not sure how that works (besides serotonin increasing dynorphin, the other way around). Could be offsetting cortisol's acute effects on SERT too. Really need to understand more.

Don't forget the wikipedia page, has some interesting starting points:
Dynorphin - Wikipedia
κ-opioid receptor - Wikipedia

Sci-Hub | Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI. Behavioural Brain Research, 327, 75–82 | 10.1016/j.bbr.2017.03.033

[I posted way too fast on a bad day so edited this about 10 times... I gotta stop reading this forum during the week lol]

 

[Homo Consumericus]

I find this aspect of the opioid network highly interesting:

-1Opioid Receptors
Kappa opioid receptors are located on dopamine axon terminals (Svingos et al., 2001).

-The κ-opioid receptor binds to the endogenous ligand, dynorphin, and acts to decrease dopamine release.151

The dynorphin/kappa opioid receptor (KOR) system is implicated in the “dark side” of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters;

Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing.

Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function.


KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals.

Feel free to leave a comment below on what you have discovered:

Which kapa opioid receptor antagonists are available from foods? 4-caffeoyl-1,5-quinide antagonizes mu opioid receptors (4-Caffeoyl-1,5-quinide in roasted coffee inhibits [3H]naloxone binding and reverses anti-nociceptive effects of morphine in mice. - PubMed - NCBI). Can other cinnamoylquinides in decaffeinated instant coffee antagonize KOR?

 

[Lokzo]

Yeah, well the thing I don't have a great grasp on is exactly how the KOR receptors sensitize/traffic (not always straightforward, at least I don't assume), and some of the fear extinguishing effects of KOR agonism aren't clear. Plus, like oxytocin and others I think its interpretation must be complicated by systemic administration of test compounds, which hit all the brain areas. Dynorphin is also at least partly response for the analgesic effects of some cannabinoids (some study or two even claimed it was entirely responsible, iirc). There is also propranolol as noted in haidut's thread and I wonder where it intersects with KOR besides its dopamine-killing power you'd expect to lower (nor)epinephrine (there is also a role for GABAA in fear extinction, and other things). In other words, I'm 99% sure this system is involved in my experiences and issues, but I can't quite tell you how.

It certainly kills off dopamine but also serotonin release:
Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking

Since it plays the part of a "failure" signal - it seems - it would be logical for it to get rid [or limit] serotonin because brain serotonin is "predictive" in function, so they seem made for different moments during a challenge. Another way to look at it is that serotonin is involved in implementing "patience" toward stressors, and you would want to lose that at the end. Cortisol also does acutely as was posted. I still have a lot more to read about this system, but experiments with fear memory are difficult to follow. Also time. This must be the first dedicated thread to this on here (?).

Edit: Forgot about this one where it actually downregulated SERT instead:
Modulation of Serotonin 1Transporter Function by kappa-Opioid Receptor Ligands

I think there is some dynamic based on the brain area and length of exposure or such, because there's a point where you expect it to "register" with the serotonin system. I'm not sure how that works (besides serotonin increasing dynorphin, the other way around). Could be offsetting cortisol's acute effects on SERT too. Really need to understand more.

Don't forget the wikipedia page, has some interesting starting points:
Dynorphin - Wikipedia
κ-opioid receptor - Wikipedia

Sci-Hub | Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI. Behavioural Brain Research, 327, 75–82 | 10.1016/j.bbr.2017.03.033

[I posted way too fast on a bad day so edited this about 10 times... I gotta stop reading this forum during the week lol]

haha legendary.

Thanks for contributing man.

I can't wait to dive into these references.

 

[Lokzo]

Which kapa opioid receptor antagonists are available from foods? 4-caffeoyl-1,5-quinide antagonizes mu opioid receptors (4-Caffeoyl-1,5-quinide in roasted coffee inhibits [3H]naloxone binding and reverses anti-nociceptive effects of morphine in mice. - PubMed - NCBI). Can other cinnamoylquinides in decaffeinated instant coffee antagonize KOR?

What a fantastic point.

The only other flavonoid I know if is Amentoflavone...

But apparently Apigenin is also good for Kappa antagonsim.


I am trying to understand whether these receptors get down-regulated in response to both AGONISM and ANTAGONISM?

 

[Homo Consumericus]

What a fantastic point.

The only other flavonoid I know if is Amentoflavone...

But apparently Apigenin is also good for Kappa antagonsim.


I am trying to understand whether these receptors get down-regulated in response to both AGONISM and ANTAGONISM?

Nice, Inaut has been going on about chamomile as a source of apigenin. I'll start drinking again.

It was my understanding that antagonists cause receptor upregulation and wiki agrees with some caveats.

 

[Randle Cyclist]

Remember those stupid YouTube videos from about 10 years ago of people smoking salvia divinorum? It's a powerful kappa agonist that results in dysphoria and unpleasant hallucinations. Iboga also is a kappa opioid receptor agonist with similar effects. Neither should be experimented with except in an attempt to resolve a severe drug or alcohol addiction. Or unless you'd like to experience a waking nightmare.

I just did some quick research and noticed that most plants in the mint family are weak K opioid agonists. Perhaps that's why they lower testosterone since messing with opioid receptors often results in hormonal shifts.

 

[Inaut]

the few trips I've had on salvia (2 or 3) were well worth it.

i saw elves

 

[Randle Cyclist]

the few trips I've had on salvia (2 or 3) were well worth it.

i saw elves

The Lord of the Rings or the Keebler kind?

 

[Inaut]

100% Keebler type. They were quite jolly :). Escorting me down a river on either side of the river bank. I was on a raft.

Yellow hats and shirts, red pants, white faced and white beards

It was weird. Was like 4d with 3D and 2D aspects to it.

No more psychedelics for me. I just come to the RPF to unhinge now.

 

[Randle Cyclist]

That is pretty funny. You were fortunate that you had a good trip. It also goes to show just how powerful of an effect kappa opioid agonists can have. Salvia sounds like the last thing I'd want to try from the experiences I've read, not to mention those YouTube videos. I like to remain lucid with coherent thoughts and speech.

Anyway, back on topic, I think playing the opioid system is a bad idea with unless addiction is involved or it's to resolve acute, debilitating pain. Chronic pain is a bit of a grey area. Many of the common opioids, from morphine to kratom, have an agonistic effect on the kappa receptors in addition to the main mu receptors.

 

[Terma]

No you do not want dynorphin or KOR agonism alone. That is how people get bad trips from THC. It can even get cytotoxic although I don't understand all the circumstances in which it becomes (besides the obvious from this study; surely it can be countered):
Nitric oxide synthase inhibitors influence dynorphin A (1-17) immunoreactivity in the rat brain following hyperthermia. - PubMed - NCBI

That said it seems to have an essential role in fear recall/extinction and quite powerful, but the power must be harnessed. I'm not sure what kind of dosage response you get with salvia however and I'd only use that with 10 other things (beyond initial diagnostics; those participate in fear processes as well anyway). Inevitably the high variability in experiences to KOR agonism is a factor of individual health/neurotransmission.

Those were epic videos, I must've laughed for 10 mins at this (the original copy got 18+'d):

100% Keebler type. They were quite jolly :). Escorting me down a river on either side of the river bank. I was on a raft.

Yellow hats and shirts, red pants, white faced and white beards

It was weird. Was like 4d with 3D and 2D aspects to it.

No more psychedelics for me. I just come to the RPF to unhinge now.

(Misses a raft)

(Okay there aren't a lot of elves in there either - he was never very good at videos... I always wanted an excuse to post that song :P. Sounds like a great experience, but I'm not looking for visuals at all either)

 

[Terma]

My friend told me that video might have been faked. Idk. It's still beautiful to me, I couldn't distinguish it, so if it is, they did a good job. I don't read youtube comments so I have no idea.

 

[morgan#1]

My friend told me that video might have been faked. Idk. It's still beautiful to me, I couldn't distinguish it, so if it is, they did a good job. I don't read youtube comments so I have no idea.

That video made me ill. I’m a girl, so maybe I’m a pus sy. Strange the things people will go to in order to escape their minds.

 

[Terma]

lol I am pretty desensitized, but if it does that for you, brings me to tears, and keeps people away from salvia, I think they achieved something. I lose it at the "don't look at me!" part. I wonder how many people living in apartments died that way (that's a serious concern :P)...

 

[bdawg]

Remember those stupid YouTube videos from about 10 years ago of people smoking salvia divinorum? It's a powerful kappa agonist that results in dysphoria and unpleasant hallucinations. Iboga also is a kappa opioid receptor agonist with similar effects. Neither should be experimented with except in an attempt to resolve a severe drug or alcohol addiction. Or unless you'd like to experience a waking nightmare.

I just did some quick research and noticed that most plants in the mint family are weak K opioid agonists. Perhaps that's why they lower testosterone since messing with opioid receptors often results in hormonal shifts.

lolll yeah i remember

once got high on nutmeg too, kappa activity there?

 

[Randle Cyclist]

lolll yeah i remember

once got high on nutmeg too, kappa activity there?

Lol how was your experience?

It's unlikely. Apparently it's fairly similar to the anticholinergics like benadryl or atropine. It hasn't been studied too much since it's toxic in high amounts and doesn't seem to have any beneficial attributes other than flavor. It's best reserved for use in pumpkin pie and eggnog.

 

[Terma]

Not sure if anyone pointed this out yet though it is pretty predictable,

Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications f... - PubMed - NCBI

Dynorphin peptides act preferentially at kappa- as well as mu- and delta-opioid receptors. This study was conducted to determine whether dynorphin peptides act to lower dopaminergic tone in the tuberoinfundibular system, resulting in elevated serum prolactin levels and, if so, whether such an effect is mediated by the opioid receptors. Dose-related increases in serum prolactin levels were observed after dynorphin A1-13 was administered i.v. in doses of 120 and 500 micrograms/kg to healthy human volunteers with no history of drug or alcohol abuse. Studies were then conducted to determine whether this effect is opioid receptor mediated and, if so, whether at kappa- or mu types. Pretreatment with the opioid antagonist nalmefene (30 mg i.v.), which has high affinity at both mu- and kappa-opioid receptors, caused a greater attenuation in dynorphin A1-13-stimulated increases in serum prolactin levels than pretreatment with similarly high doses of naloxone, an antagonist with lower affinity for both mu- and kappa-opioid receptors. These results suggest dynorphin A1-13 lowers tuberoinfundibular dopaminergic tone through action at kappa- and possibly mu-opioid receptors. Female subjects were significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and kappa-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Also, both dynorphin peptides and synthetic kappa-opioid agonists have been shown to lower dopamine levels in the nucleus accumbens and to attenuate cocaine-induced surges in dopamine levels. Thus, a dynorphin-like compound capable of reaching critical mesolimbic-mesocortical and nigrostriatal dopaminergic systems may be effective in the management of cocaine addiction.

kappa-Opioid receptor agonist-induced prolactin release in primates is blocked by dopamine D(2)-like receptor agonists. - PubMed - NCBI

Kappa-opioid receptor agonists may have pharmacotherapeutic potential in the management of psychostimulant abuse, due to their ability to modulate dopamine receptor systems involved in drug reinforcement. kappa-Opioid receptor agonists also modulate dopamine receptor function in the hypothalamic tuberoinfundibular system, which has inhibitory control over an anterior pituitary hormone, prolactin. Prolactin levels may thus be a "biomarker" for the ability of kappa-opioid receptor agonists (e.g., (+)-(5 alpha,7 alpha,8 beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]-benzeneacetamide (U69,593)) to modulate a dopamine receptor system in vivo in primates. The effectiveness of dopamine D(2)-like receptor agonists (quinpirole and (+/-)-7-hydroxy-dipropylaminotetralin (7-OH-DPAT); 0.0032-0.1 mg/kg) in preventing U69,593-induced prolactin release was studied in intact female rhesus monkeys. Quinpirole and 7-OH-DPAT inhibited U69,593-induced prolactin release (ID(50) values: 0.013 and 0.0072 mg/kg, respectively). However, the dopamine D(1)-receptor agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazapine (SKF 82958; 1 mg/kg) did not inhibit U69,593-induced prolactin release under the same conditions. In contrast, the largest doses of quinpirole or 7-OH-DPAT presently studied (0.1 mg/kg), did not decrease sedation caused by U69,593 (0.01, 0.032 mg/kg), a prominent effect of centrally penetrating kappa-opioid receptor agonists. The sedative effect of U69,593 (0.032 mg/kg) was prevented by naltrexone (0.32 mg/kg), consistent with kappa-opioid receptor mediation of this effect. These studies suggest that prolactin release is a valid biomarker for the ability of kappa-opioid receptor agonists to modulate dopamine D(2)-like receptor function, and may also be used to quantify dopamine D(2)-like receptor agonist potency in primates.

 

[casualty0]

To illuminate your q?

I am trying to understand whether these receptors get down-regulated in response to both AGONISM and ANTAGONISM?

Look into Bupenorphine - which putatively "treats" opiate withdrawal. BUP contains a KOR antagonist, but only partially agonize the good opiate receptors.

My sketchy understanding is the FDA mandates "Designer Drugs" as punitive measure upon its unhappy ho$tages.