709 replies to this topic

[socialpiranha]

anyone interested in a group buy of the kappa opioid antagonist jdtic ? I found a trustworthy source, its expensive but if we get enough ppl and buy enough it would make it a lot cheaper. anecdotal evidence suggests its highly effective for ppl with endogenous depression and social motivation issues. apparently jdtic permanently binds to the receptor so you dont have to redose until your body resynthesizes new receptors

[extroverinstinct]

The only thing I can say it OUCH!
Dynorphin is 6 to 10 times more potent than morphine at producing analgesia. I use a kappa agonist on a daily basis for various reasons, and it kills any and all pain you could possibly feel from normal activities as well as helps with sleep.(and if I ever get a chance to find out if it works on acute pain I'll let you know). It is true If I take too much the depression that follows is, well, like nothing you would ever wish to experience but I have the dose exactly right now.
Aren't you worried about hyperalgesia???? The thought of it makes me tremble.

[socialpiranha]

The thought crossed my mind because i know dynorphin does alleviate a very specific type of pain, allodynia but i didnt notice any of that with buprenorphine and anecdotal reports of jdtic dont mention anything about any type of hyperalgesia or allodynia. Can i ask you what type of pain you use the agonist for ? is it salvia d or something else? is it possible whatever substance your using has agonistic properties at the mu receptor in smaller doses and only antagonizes the k receptor at higher doses?

[Olon]

Thymoquinone from black onion seed very likely has an indirect stimulation of kappa opioid receptor.
http://www.ncbi.nlm....pubmed/10913589
Someone who is considering whether he/she should join the group buy could test the depressogenic effect of black onion seed oil for demonstration.

Edited by Olon, 22 May 2013 - 07:02 AM.

[Olon]

This sounds paradoxical to me:
http://www.ncbi.nlm....pubmed/23178563
But in contrast to jdtic hesperidin is dirt cheap.

Edited by Olon, 22 May 2013 - 07:16 AM.

[lourdaud]

I'm definitely interested!

[extroverinstinct]

The thought crossed my mind because i know dynorphin does alleviate a very specific type of pain, allodynia but i didnt notice any of that with buprenorphine and anecdotal reports of jdtic dont mention anything about any type of hyperalgesia or allodynia. Can i ask you what type of pain you use the agonist for ? is it salvia d or something else? is it possible whatever substance your using has agonistic properties at the mu receptor in smaller doses and only antagonizes the k receptor at higher doses?

I use hesperidin. It doesn't have effects at the Mu receptor. It activates Kappa receptors and may have potential at adenosine receptors. Quite frankly I never experienced near the therapeutic effect from salvia that I receive from hesperidin. I use it for joint pain and everday aches. It's much more powerful than codene or morphine are as far as analgesia is concerned. As for the dosage used I couldn't tell you. I actually eat lemon peels lol. 1 lemon peel, with the outter skin grated off, kills pain helps me sleep and doesnt cause depression the next day. Two peels knocks me out and makes me feel flat the next day. Once I ate 4 peals to get a sense of how it would affect me. I felt terribly depressed the next day, I mean HORRIBLY DEPRESSED. BLACK HOLE END OF THE WORLD WORTHLESS DEPRESSED. The whole time this lasted I was also very tired and able to fall asleep with no problem whatsoever, which was preferable to the helplessness I felt.
If you run out of painkillers(I have lupus) than 1 or 2 lemon peels twice daily will get rid of the aches, chills, shakes, sweats, diahrea and high blood pressure associtated with withdrawal, well this is all how it worked for me. I can't say it will affect others like this at all.

Edited by extroverinstinct, 24 May 2013 - 04:59 AM.

[socialpiranha]

Thats interesting extroveri, I might have to give that a try sometime. i know lemon oil is a 5ht1a agonist so that could have something to do with it too

lourdaud i'll msg ya later!

[extroverinstinct]

I'm also wondering couldn't a kappa antagonist reinstate seeking behavior in addiction possibly? I understand agonists can prevent seeking behavior with cocaine and opiates. I really can't wait for the results of this trial! If there is no hyperalgesia or reinstatement of seeking bheavior then this could truly be a breakthrough for depression and dysphoria!

[Olon]

The problem I see for "exotic" antidepressive mechanism is the following:
The blockbuster is suitable for 50% of the patients. Now assume that the "exotic" drug is effective in 30%. Among the blockbuster non-responders there are probably some totally therapy resistant cases, so let's assume the exotic drug works for 20% of them. The result is a drug for 10% of the patients.
But what one could ask in the context of kappa opioid receptor antagonists:
Naloxone and naltrexone are effective against dissociation and self-harm in borderline personality disorder (due to kappa opioid receptor antagonism?), so one might be able to benefit from "orphan disease" regulations and later expand the indication for therapy-resistant depression. This is done for cancer drugs: Take a rare cancer where you are sure it works, and later try to expand the indication.

[socialpiranha]

I'm also wondering couldn't a kappa antagonist reinstate seeking behavior in addiction possibly? I understand agonists can prevent seeking behavior with cocaine and opiates. I really can't wait for the results of this trial! If there is no hyperalgesia or reinstatement of seeking bheavior then this could truly be a breakthrough for depression and dysphoria!

The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety
http://www.ncbi.nlm....pubmed/22515275

The dynorphin/kappa opioid receptor system: a new target for the treatment of addiction and affective disorders?
http://www.nature.co...pp2008165a.html

alks 5461 is a combination of buprenorphine and samidorphan whose phase 2 trials went very well
http://www.businessw...hase-2-Clinical

[socialpiranha]

The problem I see for "exotic" antidepressive mechanism is the following:
The blockbuster is suitable for 50% of the patients. Now assume that the "exotic" drug is effective in 30%. Among the blockbuster non-responders there are probably some totally therapy resistant cases, so let's assume the exotic drug works for 20% of them. The result is a drug for 10% of the patients.
But what one could ask in the context of kappa opioid receptor antagonists:
Naloxone and naltrexone are effective against dissociation and self-harm in borderline personality disorder (due to kappa opioid receptor antagonism?), so one might be able to benefit from "orphan disease" regulations and later expand the indication for therapy-resistant depression. This is done for cancer drugs: Take a rare cancer where you are sure it works, and later try to expand the indication.

I understand what your saying, but the blockbuster drugs are only slightly better than placebo so its basically people who would have responded to placebo plus a very small percentage 10% roughly, who wouldnt respond to placebo who benefit from ssri's etc. This does not mean that a more direct acting drug would not be more effective for both ssri responders as well as non responders.Not to mention side effects. This is not an exotic mechanism either all antidepressants effect creb and dynorphin just indirectly.

[Doktor]

Unless I am missing something obvious here, JDTic shouldn't be that expensive really.

You guys ever hear of David Pearce? He's a pretty well known dude; he's currently dosing JDTic at 100mg a day... So first off, the human dose could be pretty damn low.
Then, you need to consider the fact that it is a permanent antagonist... your brain will not be binding to any Kappa agonists for a week or longer after you dose this drug. Therefore, it would seem logical to dose this once a week or so... maybe twice.

If this drug really only requires this type of low and infrequent dosing, it's not expensive at all really.

One thing you might want to consider though; if it antagonizes the Kappa receptor to a high degree, then it will very likely up-regulate the shit out of your KORs as well. When you stop taking this drug, you may very well be in for a withdrawal even worse then then opiates. I have been through I.V heroin withdrawal myself, and by reading about the way this opiate system works, it does not sound like you want to up-regulate the Kappa system, even to the slightest magnitude...

[socialpiranha]

Yeah david pearce was trying it at 100 micrograms a day, I can't find any up to date information from his anecdotal trial yet. At that dosage it would be quite cheap. I don't know if upregulation would be a problem or not...all we can really go on is anecdotal reports. I have been through opiate withdrawal as well and wouldn't wish it on my worst enemy. I have gone cold turkey from oxycontin, methadone and buprenorphine separately. buprenorphine was no harder than methadone or oxycontin but withdrawals lasted longer than oxy and about the same as methadone. Buprenorphine is a fairly active kappa antagonist but i don't think it adds anything to the withdrawal.

[Doktor]

Hmm, that's a good point about Buprenorphine... I just can't help but think that the "no free lunch" rule would apply here as well.

[socialpiranha]

I have a feeling your right to an extent but to what extent is the question. i'm sure there will be side effects i'm less sure about withdrawal because the kappa receptor is so different than the mu. Also both antagonists and agonists of the kappa receptor have been shown to attenuate withdrawal and addiction, so any homeostatic actions may not be as "heinous" as mu up/down regulation.

Trialling it is not for the faint of heart but for those of us who are willing to be the guinea pigs , the possibility of total remission of anxiety/depression/ocd/addiction is well worth the risk.

If there were another drug available online which hadn't been thoroughly pioneered i would be all over it.

Bpap is in the works (yadayada et al) but if itenhances natural release it would stand to reason it could just exacerbate already abnormal function

7,8 dihydroxyflavone looks promising in animals but anecdotal reports are less impressive

[socialpiranha]

Is anyone on here in a position to place orders from chemical companies who only ship to companies or universities etc? I have only been able to find two suppliers, The guy who runs the jdtic website(sort of sketched out about that plus he only takes bitcoin) and medchemexpress who haven't gotten back to me and say on their site they only ship to uni's and companies.

Edited by socialpiranha, 03 July 2013 - 01:25 AM.

[Cosma]

Hi socialpiranha,
I have specifically registered on this site to tell you i have same interest as yours to try getting my hands on some JDTic.
I have been suffering from GAD for the past 10 years or so and after trying pretty much everything the medical community have to offer at this point, it's time for me to try finding my cure somewhere else.

So far the best offer i got is $350 for 100 grams which is far more than i (and probably you) need for our test.
If you or anyone else here are still interested we can try to arrange a group buy of some sort.

I'm also very interested to know if anyone have any new information on a new research being made on the substance, or any info on why the last one was terminated.

[socialpiranha]

Hey cosma, that is an amazing price, the best i could find is 130$ for 5 MILLIGRAMS....would you mind posting a link for that source?

[Cosma]

I can't post links but the offer still stands, so if any of you are interested please contact me or socialpiranha.

[addx]

My take on this and I have read 1000s of studies which led me to this. I will not post them as I didn't keep track, but if anyone finds anything suspicios point it out and I'll try and find proof again.

Mu and kappa opiod networks facilitate the basic reward/fear system.
Kappa opioid receptors(KOR) when activated shutdown dopamine in mesolimbic structures = this is the main cause of anhedonia
Kappa opioid receptors upregulate when there is too much dopamine in mesolimbic structures. They do this to tame the neurotoxic dopamine levels. You become more fearful/anxious and this counteracts the extra dopamine from whatever you're pushing into your system(cocaine, morphine)
Thus, kappa opioid network is the main network responsible for facilitating drug tolerance and withdrawal.
Once the drug use is stopped the kappa opioid network remains upregulated causing fear/anxiety(and not even having a source origin as in an event since the the cause was chemical). This state leads to drug relapse.
Tha kappa opioid network downregulates slowly, painfully slowly.
Obviously the only way to force downregulation is to agonize the shit out of it.
Thus, the only know substances to actually reverse tolerance are kappa opioid agonists.
Only known methods are salvia divinorum or ibogaine. Perhaps low dose ketamine could do it, ketamine does agonize kappa and I fear that the known ketamine afterglow glow effect is due to KOR downregulation, just as is Salvias and Ibogaines. Ibogaine has the extra merit of its metabolite noribogaine I think is an antagonist. So after Ibogaine downregulates it, the metabolite disables it for months.
Kappa antagonists on the other hand should not downregulate KORs it but should simply instantly stop the effect of it being upregulated. Kappa antagonists should immediately kill withdrawal.
Having said that, JDTic as a kappa antagonist infact in a way does downregulate KORs. It corrupts them. Thus the long effect. JDTic AFAIK corrupts receptors so its effects last until your brain grows new ones.
As far as mental health is concerned, most mental disorders are fear/anxiety fueled, these are people who have their kappa opioid system upregulated due to trauma, abuse or genetics. Thus, these chemicals are invaluable to treat the entire pallete of mental disorders.
The list starts with anxiety, anhedonia, depression, compulsions and goes on...
Fear causes anxiety. Anxiety is dopamine in the fear system. Fear also kills dopamine in the reward system. After a while the anxious dopamine causes downregulation of the fear-dopamine channels at which point you become less anxious and more lifeless, learned helplessness. So, you become a zombie, your reward dopamine is locked out by fear. And the same fear can't even produce dopamine to provide anxiety, just lethargy and anhedonia.
As you see, dopamine is just the perception-drive neurotransmitter, be it drive to approach or avoid. Thus stimulants cause anxiety more often than reward and prolonged use causes upregulation of KOR system killing dopamine in mesolimbinc structures leaving the stimulants to increase dopamine only for anxiety purposes eventually leading to paranoia.
The only question is, does the mu opioid system upregulate to counter anxiety-dopamine is does the numbing of anxiety only facilitated by dopamine receptor downregulation. If it does then antagonizing KORs in a state of upregulated MOR would lead the person into mania. This interplay might be the mechanism of bipolar as it obviously provides the mechanism for depression/anhedonia.

[socialpiranha]

interesting, kappa antagonists were being trialled for bipolar depression...i think it was either lily or astra zeneca...unfortunately they were pumping high doses into animals to test for toxicity and subsequently aborted the trials after they noticed some toxicity...doses were not comparable at all though.

[addx]

and kappa agonists were tested to see if they stop acute mania and they do.

kappa agonists also block cocaine reward

opioids influence mood rapidly and robustly and without strange sideeffects of dopaminergics of sertonoergics.

they are mainly responsible for mood and in them lies the answer to most issues. it is really sad it takes them so long to figure this out.

what else did they think would influence mood other than the reward fear system? seeing possibilities of rewards makes you elated and even fearless. seeing possibilities of stress makes you anxious and also anhedonic. this is simple as 1-2-3.

mu opioids always cause better mood.
kappa opioids always cause worse mood.

no other neurotrasmitter is THAT precise in mood control in the sense that it doesn't cause any other weird effects.


dopaminergics can increase reward perception as much as anxiety perception. it's just a "drive/perception/focus control" network. pushing it causes all kinds of sideeffects.
serotonergics are even more weird, they seem like a "purge" neurostramitter type network(purge bowels, purge/integrate memories to subconscious? not sure). and cause even more sideeffects
noradrenergics make you nervous, stimulate the HPA, make you angry etc..

point is, they're messing with "drive", dopamine and/or noradrenaline , not the source or "direction" of the drive.

increasing dopamine increases perception of fear and desire alike. as does oxytocin increase distrust as much as trust. obviously there's another network(although it might also be a part of opioid network) that facilitates is someone trusted or not. oxytocin only multiplies/amplifies this "value". dopamine does this for fear/desire - multiplies/amplifies it.

Edited by addx, 12 August 2013 - 09:12 AM.

[addx]

This is from the book 'Behavioral of Bipolar disorder and its treatment'

In humans, the partial kappa agonist pentazocine was tested adjunctively in ten individuals with BPD during a manic episode. In this uncontrolled study patients received 50mg doses 2h apart. Manic symptoms were reduced within 1 hour after each dose, 44% after the first and 41% after the second dose. The results suggest that this agent improved manic symptoms without inducing depression.

Kappa agonists do infact induce depression. So what I'm reading from this is that the manic episode is caused by KOR downregulation. Pushing more kappa agonists onto a manic patient would have to induce depression at some point. If there would be no other sideeffects up to that point - that would mean this mechanism is precisely the mechanism that causes it.

[addx]

And here's a nice link

http://www.ncbi.nlm....pubmed/18395712

Depleting serotonin causes kappa opioid agonists failure to inhibit cocaine effects. I would that in that situation suspect kappa opioid receptors upregulate even further in an effort to try and control reward pathways neurotoxic dopamine levels. Providing serotonin enables kappa opioid network to produce its effects and reduces the need for it to upregulate. That's what I read from this, but it is jumping to conclusions.

My point is trying to link up the iffy efficacy of serotonin for depression/anxiety.

Ok, lets do some more

http://www.ncbi.nlm....pubmed/20939060

Acute activation of κ-opioid receptors (KOR) decreases dopamine (DA) extracellular levels in both the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Also, the acute activation of KOR prevents alterations in behavior and neurochemistry occurring after repeated use of psychostimulants. Opposing to the acute effects, repeated administration of the KOR agonist, U-6593, potentiates both high-potassium and amphetamine induced DA release in the NAc, suggesting that repeated activation of KOR sensitizes mesolimbic dopaminergic neurotransmission. This study investigated the effect of repeated treatment with U-69593 on basal and stimulated DA and serotonin (5HT) extracellular levels in the rat mPFC. Rats were injected once daily with U-69593 (0.16-0.32 mg/kg) or vehicle for 4 days. One day after the last injection, microdialysis experiments assessing DA and 5HT extracellular levels in mPFC were conduced. The repeated treatment with U-69593 significantly augmented potassium-stimulated DA extracellular levels, without affecting potassium-stimulated 5HT extracellular levels, suggesting an increase in DA releasability.

IMO this basicly says: kappa opioid agonists fix anhedonia(dopamine levels in mesolimbic structures) through periodical dosing. (remember what I wrote: salvia divinorum weekly/biweekly)

[addx]

Not very interesting but still another study that proves the mechanism: http://www.ncbi.nlm....pubmed/19859697


But here we go in longecity style:

Knockdown of prodynorphin gene prevents cognitive decline, reduces anxiety, and rescues loss of group 1 metabotropic glutamate receptor function in aging. http://www.ncbi.nlm....pubmed/23904614

Prodynorphin is the precursor to dynorphin - the endogenous kappa opioid ligand


More,

Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled

http://www.ncbi.nlm....pubmed/23836029


More

Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction.
http://www.ncbi.nlm....pubmed/23751206


And more rats

Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI
http://www.ncbi.nlm....pubmed/23731692

nor-BNI is kappa opioid antagonist



There is tons of studies confirming all this.. that's it for now, I'll add more later

[addx]

More rats

Kappa opioid receptor signaling in the basolateral amygdala regulates conditioned fear and anxiety in rats.
http://www.ncbi.nlm....pubmed/21531393


Blockade of kappa opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats
http://www.ncbi.nlm....pubmed/21736885


This one just to connect to the standard benzo anxiety treatment:

Presynaptic inhibition of gamma-aminobutyric acid release in the bed nucleus of the stria terminalis by kappa opioid receptor signaling
http://www.ncbi.nlm....pubmed/22225848

GABA is just an infrastructure network. KOR inhibits GABA. So taking GABAergics is fixing the issue downstream of the source. As are dopaminergics and serotonergics.


One for the topic at hand:

The kappa opioid receptor antagonist JDTic attenuates alcohol seeking and withdrawal anxiety.
http://www.ncbi.nlm....pubmed/22515275


One summary study saying exactly what I'm saying:

Addictions to cocaine or heroin/prescription opioids [short-acting μ-opioid receptor (MOPr) agonists] involve relapsing cycles, with experimentation/escalating use, withdrawal/abstinence, and relapse/re-escalation. κ-Opioid receptors (KOPr; encoded by OPRK1), and their endogenous agonists, the dynorphins (encoded by PDYN), have counter-modulatory effects on reward caused by cocaine or MOPr agonist exposure, and exhibit plasticity in addictive-like states. KOPr/dynorphin activation is implicated in depression/anxiety, often comorbid with addictions. In this opinion article we propose that particular stages of the addiction cycle are differentially affected by KOPr/dynorphin systems. Vulnerability and resilience can be due to pre-existing (e.g., genetic) factors, or epigenetic modifications of the OPRK1 or PDYN genes during the addiction cycle. Pharmacotherapeutic approaches limiting changes in KOPr/dynorphin tone, especially with KOPr partial agonists, may hold potential for the treatment of specific drug addictions and psychiatric comorbidity.
http://www.ncbi.nlm....pubmed/22709632



Another withdrawal, this time nicotine

Chronic nicotine enhanced the affective, anxiogenic, and neurochemical effects produced by KOR activation in adult rats. Our data suggest that chronic nicotine elicits an increase in KOR function, and this may contribute to nicotine withdrawal since KOR activation facilitated and KOR blockade prevented withdrawal signs upon removal of nicotine.
http://www.ncbi.nlm....pubmed/22659976


One general, proving that dynorphin regulates fear acquiring and extinction:

Dynorphins regulate fear memory: from mice to men.
http://www.ncbi.nlm....pubmed/22764240

[addx]

Antidepressant-like effects of kappa-opioid receptor antagonists in Wistar Kyoto rats.
http://www.ncbi.nlm....pubmed/19924112


Another summary study:

Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive-like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both.
http://www.ncbi.nlm....pubmed/19782055



AAAAnd I didnt read this study before writing all this but here it is, like someone read my threads from various forums:

The dynorphin-like peptides have profound effects on the state of the brain reward system and human and animal behavior. The dynorphin-like peptides affect locomotor activity, food intake, sexual behavior, anxiety-like behavior, and drug intake. Stimulation of kappa-opioid receptors, the endogenous receptor for the dynorphin-like peptides, inhibits dopamine release in the striatum (nucleus accumbens and caudate putamen) and induces a negative mood state in humans and animals. The administration of drugs of abuse increases the release of dopamine in the striatum and mediates the concomitant release of dynorphin-like peptides in this brain region. The reviewed studies suggest that chronic drug intake leads to an upregulation of the brain dynorphin system in the striatum and in particular in the dorsal part of the striatum/caudate putamen. This might inhibit drug-induced dopamine release and provide protection against the neurotoxic effects of high dopamine levels. After the discontinuation of chronic drug intake these neuroadaptations remain unopposed which has been suggested to contribute to the negative emotional state associated with drug withdrawal and increased drug intake.
http://www.ncbi.nlm....pubmed/19804796



And for all ADHD treated kids:

Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate.
http://www.ncbi.nlm....pubmed/18923399


So there, we have it all covered, all addictions, depression, anhedonia and anxiety. And the underlying mechanism. And even some relations to why current medication semi-works.

Wooohoo...

Can I get a prize?

[addx]

Prodynorphin-derived peptides are critical modulators of anxiety and regulate neurochemistry and corticosterone
http://www.ncbi.nlm....pubmed/18800067


Anxiolytic-like effects of kappa-opioid receptor antagonists in models of unlearned and learned fear in rats.
Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders
http://www.ncbi.nlm....pubmed/17823306

[socialpiranha]

Awesome post addx I've seen most these studies and and noticed the same vein running through them all. Dopamine noradrenaline serotonin and many other neurotransmitters/peptides/etc are very much involved too imo, it's just that targetting the kor's is just much closer to the root of the issue so the downstream effects on other systems are naturally affected positively. The more reward specific the receptor the closer you get to the problem and the kor is by far the closest thing we know of.

Kappa agonism triggers creb induced inhibition of dopamine release in reward centers whereas antagonism subsequently stimulates release. This is a very simplified model but a very reward specific effect none the less. This function aligns most closely with our everyday experience of feeling good or bad. This sequence/function (seems) to be what is happening when a good experience is rewarding and a bad one is not. Whatever the reason for the reward system being broken or even just suboptimal, the kor is by far the most promising target in any and all reward related disorders...Which is the majority of psychiatric disorders at least in part.