Kappa Opioid Blockade in addiction treatment?

[Neuroprotection]

Kappa opioid receptors are important in addiction due to their ability to suppress reward, induce anxiety/depression, impair cognition and possibly contribute to psychotic symptoms. my posts usually turn into essays, so I won’t go into any more detail about all their mechanisms unless anyone requests it. just note that one of the main mechanisms is suppression of dopamine release in the nucleus accumbens. it is thought that a buildup of Dynnorphin during chronic psychostimulant or opioid use Continues to overstimulate kappa receptors contributing to long-term post-withdrawal anhedonia and depression. this creates a sense of hopelessness and despair, which makes sobriety feel pointless. this is why kappa antagonists have proved so promising in animal and human studies. they are by no means A solution/cure for addiction. rather, they could be useful tools to block behavioural despair and assist those who truly want to quit drug use in their journey. for those that don’t intend to quit, or are struggling to make that decision, Kappa antagonism should still alleviate despair/depression and anhedonia which caused many drug users to withdraw from daily life activities and their Family/social circles. furthermore, if animal studies are correct, it should also suppress further escalation of drug intake, A phenomenon linked to reward suppression by the kappa opioid receptor.

Unfortunately, highly selective Long acting Kappa antagonists aren’t yet approved for human use but a combination of naltrexone and buprenorphine is believed to be rather effective. buprenorphine has strong kappa antagonist effects, whilst the addition of naltrexone prevents Mu receptor activation by buprenorphine thus eliminating the potential for abuse and addiction. if I remember correctly, this combination lifted mood and eliminated depression in a set of abstinent heroin users according to an article I read.
Does anyone have experience with this?

 

[AlphaMethylPhenyl]

No personal experience but I've known people who've been on bupe. I thought that bupe was a mu partial. Imagine that the naltrexone doesn't entirely negate the bupe mu agonism, though, in any case, especially outside the cns. I think it's pretty clear that, because of it's sort of unique pharmacological profile, it can be an effective depression/anxiety/psychosis treatment in some, counter to classical opioids. Dynorphin it iself a mu agonist as well, pretty sure. But I know that ibogaine blocks the kappa subtype, just not sure how strongly, and of course it has some data behind it for hard drug addiction. Other than that, salvia, lol, which is mostly a selective kappa agonist, but it's starting to get some positive data as well, I think (salvinorum A). Dunno how that figures out neurobiologically. Maybe agonists and antagonists alike downregulate the receptor, akin to 5-HT2a partials and 5-HT blockers (Atypical ap's)?

 

[someguyontheinternet]

Kappa opioid antagonism is also an interesting target for treating stress related disorders like some MDD and PTSD. A thought I had was what if we can target something in the GRK3/beta arrestin pathway to induce KOR endocytosis for both SUD and stress disorder patients who might have upregulated KOR

 

[Neuroprotection]

No personal experience but I've known people who've been on bupe. I thought that bupe was a mu partial. Imagine that the naltrexone doesn't entirely negate the bupe mu agonism, though, in any case, especially outside the cns. I think it's pretty clear that, because of it's sort of unique pharmacological profile, it can be an effective depression/anxiety/psychosis treatment in some, counter to classical opioids. Dynorphin it iself a mu agonist as well, pretty sure. But I know that ibogaine blocks the kappa subtype, just not sure how strongly, and of course it has some data behind it for hard drug addiction. Other than that, salvia, lol, which is mostly a selective kappa agonist, but it's starting to get some positive data as well, I think (salvinorum A). Dunno how that figures out neurobiologically. Maybe agonists and antagonists alike downregulate the receptor, akin to 5-HT2a partials and 5-HT blockers (Atypical ap's)?

I think doses of naltrexone used in the combination are around 50 mg or higher, likely blocking any MU activation even from strong full agonists, let alone the partial agonist buprenorphine. not saying you’re wrong, as different combinations may utilise different doses of naltrexone and buprenorphine. regarding Ibogaine, The bulk of hallucinogenic effects are attributed to 5HT2A agonism with considerable contributions from NMDA antagonism and kappa opioid receptor activation. Salvinorin A it’s truly unique both because of its structure and it’s very high selectivity for the kappa opioid receptor. I agree with you, it is quite possible that Kappa receptor activation could result in receptor down regulation thus improving long-term mood. i’m also wondering if The chronic dysphoria caused by Kappa activation can enhance the value of reward and give way to a newly appreciated sense of pleasure once it subsides.

Kappa opioid antagonists are certainly promising for stress resilience and trauma treatment. according to some studies, it is theorised that best results would be obtained if the drugs are administered before a stressful event, but would very likely be useful if administered afterwards as well. however, they might then have to be administered for longer to achieve maximum results.

 

[Neuroprotection]

Kappa opioid antagonism is also an interesting target for treating stress related disorders like some MDD and PTSD. A thought I had was what if we can target something in the GRK3/beta arrestin pathway to induce KOR endocytosis for both SUD and stress disorder patients who might have upregulated KOR

Yes, you’re right, Kappa Opioid blockade is an important avenue of research for stress resilience and depression treatment. unfortunately, modulating receptor proteins in the way you mentioned might be a very long way off coming into clinical practice. i’m not really into conspiracy theories, but I do believe pharmaceutical companies are quite happy with their current minimally effective but highly addictive/habit-forming psychiatric medications and I’m sure they will continue to pump out new modifications of these for the near future.