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Dr. Bob is Robert Hsiung, MD,
[email protected]Shown: posts 1 to 17 of 17. This is the beginning of the thread.
Posted by linkadge on May 28, 2008, at 11:04:07
So apparently kappa opioid receptor agonism can cause depression by inhibiting the release of dopamine in the neucleus accumbens.
Stress increases the levels of dynorphin in the neucleus accumbens which is a agonist at kappa opiod receptors.
Buprenorphine is a fairly potent kappa antagonist.
Exercise decreases dynorphin levels in the neucleus accumbens (antidepressant effect?)
Also the TCA's appear to decrease dynorphin levels.Anyhow sounds like an interesting target for mood disorders. Anyone have any input?
Linkadge
Posted by undopaminergic on May 28, 2008, at 11:10:26
In reply to stress, dynorphin, kappa opioid receptors, posted by linkadge on May 28, 2008, at 11:04:07
>
> Anyhow sounds like an interesting target for mood disorders. Anyone have any input?
>
> Linkadge
>See my post of 22nd May to this board on the topic of kappa-opioid receptors:
http://www.dr-bob.org/babble/neuro/20080418/msgs/830482.htmlAlso check out the Suboxone thread on the Medication board, where i describe my recent experience with buprenorhpine.
Posted by Phillipa on May 28, 2008, at 12:17:49
In reply to stress, dynorphin, kappa opioid receptors, posted by linkadge on May 28, 2008, at 11:04:07
Well mine is far from scientific but it looks like it says excercise can cause depression by inhibiting release of dopamine so what is dynorphin which can increase depression? Phillipa
Posted by linkadge on May 29, 2008, at 15:29:22
In reply to stress, dynorphin, kappa opioid receptors, posted by linkadge on May 28, 2008, at 11:04:07
I wonder if there is any other way to modulate either dynorphin or opiate kappa receptors.
Linkadge
Posted by iforgotmypassword on June 3, 2008, at 10:15:59
In reply to stress, dynorphin, kappa opioid receptors, posted by linkadge on May 28, 2008, at 11:04:07
http://opioids.com/kappa/kappa-dopamine.html
if kappa agonism can prevent dopaminergic projection into the prefrontal cortex, it may be a significant cause of executive functioning issues?
(i want to try naltrexone, but i worry its lack of selectivity, and the fact that it is very old and concrete knowledge of it's carcinogenic potential is just not there, making the idea of long term use seem a bit creepy. sigh.)
Posted by undopaminergic on June 3, 2008, at 13:06:15
In reply to 2006 article, posted by iforgotmypassword on June 3, 2008, at 10:15:59
> http://opioids.com/kappa/kappa-dopamine.html
>
> if kappa agonism can prevent dopaminergic projection into the prefrontal cortex, it may be a significant cause of executive functioning issues?
>Yes, I think so, and I've noted a remarkable improvement of executive function after adding buprenorphine - the most potent kappa-antagonist in clinical use - to my regimen of methylphenidate and guanfacine.
> (i want to try naltrexone, but i worry its lack of selectivity, and the fact that it is very old and concrete knowledge of it's carcinogenic potential is just not there, making the idea of long term use seem a bit creepy. sigh.)
>While I'm not particularly worried about its carcinogenic potential, I'm highly suspicious of its antagonism of mu-opioid receptors, as this may reduce dopamine release especially in the nucleus accumbens.
Posted by iforgotmypassword on June 3, 2008, at 15:08:34
In reply to Re: 2006 article, posted by undopaminergic on June 3, 2008, at 13:06:15
> > http://opioids.com/kappa/kappa-dopamine.html
> >
> > if kappa agonism can prevent dopaminergic projection into the prefrontal cortex, it may be a significant cause of executive functioning issues?
> >
>
> Yes, I think so, and I've noted a remarkable improvement of executive function after adding buprenorphine - the most potent kappa-antagonist in clinical use - to my regimen of methylphenidate and guanfacine.
>
> > (i want to try naltrexone, but i worry its lack of selectivity, and the fact that it is very old and concrete knowledge of it's carcinogenic potential is just not there, making the idea of long term use seem a bit creepy. sigh.)
> >
>
> While I'm not particularly worried about its carcinogenic potential, I'm highly suspicious of its antagonism of mu-opioid receptors, as this may reduce dopamine release especially in the nucleus accumbens.i don't know how easily i could get a buprenorphine rx. it's the most potent kappa antagonist in clinical use? how low can you go and still have the ideal amount of kappa antagonism needed? what are it's other effects/affinities at a kappa-blocking dose?
i figure i could at least try naltrexone, unless someone knows how to get nor-binaltorphimine...
i have to admit i know nothing about the mu receptor, or the NAc, or what cognitive or neuropsych functions depend on dopaminergic activity in the NAc (as opposed to the PFC.)
ugh. headache.
Posted by iforgotmypassword on June 3, 2008, at 18:10:51
In reply to Re: 2006 article » undopaminergic, posted by iforgotmypassword on June 3, 2008, at 15:08:34
talked to my doctor on the phone after last message.
he said he was recently in contact with a colleague of his who treats addictions and refuses to use naltrexone due to the side effects. i brought up buprenorphine and he wasn't completely wierded out, but he also wasn't familiar with the drug.
i see him on thursday. my mission is to gather articles or reliable reading material that would support a buprenorphine rx, or a naltrexone rx.
my concern is that the ideal kappa antagonism from buprenorphine may not be acheivable without significant mu agonism. (opinions?) does it have any other receptor affinities to worry about?
looking on wikipedia, they mention:
"However, psychological distress is currently not an approved indication for the use of any opioid, and legally it falls in a "grey zone" that is technically legal but a doctor could still face charges regardless (but not for off-label scripting in itself, simply being singled out by the USA's Drug Enforcement Administration (DEA), who prosecute doctors often for using controlled substances for approved uses ("too much")).[8][9]"whoever wrote that, are they making sense?
somehow i worry that on thursday my doctor will have been on wikipedia and seen this, and not be behind the buprenorphine idea...
i'll have to find something supporting that it can be used safely without causing addiction.
Posted by iforgotmypassword on June 3, 2008, at 18:24:00
In reply to Re: 2006 article, posted by iforgotmypassword on June 3, 2008, at 18:10:51
http://en.wikipedia.org/wiki/Kappa_Opioid_receptor
"Kappa agonism is neuroprotective against hypoxia/ischemia; as such, kappa receptors may represent a novel therapeutic target."
does this mean that kappa agonism is something the brain naturally relies on to protect itself, perhaps just from everyday stuff and not stuff as blatantly harmful and obvious as hypoxia? could there be risks associated with interrupting kappa agonism in the brain? might it even possibly be neurodegenerative?
Posted by undopaminergic on June 4, 2008, at 4:11:14
In reply to Re: 2006 article, posted by iforgotmypassword on June 3, 2008, at 18:10:51
>
> i see him on thursday. my mission is to gather articles or reliable reading material that would support a buprenorphine rx, or a naltrexone rx.
>The article about buprenorphine for refractory depression can be found by following one of the links listed in the message at:
http://www.dr-bob.org/babble/20080528/msgs/831995.htmlAnother document - an editorial - mostly regarding the reasons why buprenorphine isn't likely to become an FDA-approved treatment for depression, can be found at:
http://web.archive.org/web/20031118092749/http://www.sciencething.org/Callaway.pdf> my concern is that the ideal kappa antagonism from buprenorphine may not be acheivable without significant mu agonism. (opinions?) does it have any other receptor affinities to worry about?
>Mu-agonism has a range of effects - some of them may be highly desirable, while others may be neutral or troublesome. Some effects will be noted only initially, while certain others will persist throughout treatment. Start at a low dose and titrate according to effect and tolerability.
> looking on wikipedia, they mention:
> "However, psychological distress is currently not an approved indication for the use of any opioid, and legally it falls in a "grey zone" that is technically legal but a doctor could still face charges regardless (but not for off-label scripting in itself, simply being singled out by the USA's Drug Enforcement Administration (DEA), who prosecute doctors often for using controlled substances for approved uses ("too much")).[8][9]"
>
> whoever wrote that, are they making sense?
>It's not really accurate. The DEA focus on doctors prescribing large quantities of controlled substances, and whom they suspect not to be following regulations - e.g. being overly careless about whether the drugs prescribed seem likely to be abused or sold ("diverted"). If the doctor can provide credible justification and documentation for his practices, he/she is less likely to be prosecuted.
It is extremely unlikely that the DEA would target someone who prescribes buprenorphine once in a while.
>
> i'll have to find something supporting that it can be used safely without causing addiction.
>Is is very safe, and while there's a definite risk of physical dependence, addiction is not likely - unless you have a propensity for abusing drugs - e.g. dissolving and injecting tablets.
Posted by undopaminergic on June 5, 2008, at 8:03:30
In reply to Re: 2006 article » undopaminergic, posted by iforgotmypassword on June 3, 2008, at 15:08:34
> > > http://opioids.com/kappa/kappa-dopamine.html
> > >
> > > if kappa agonism can prevent dopaminergic projection into the prefrontal cortex, it may be a significant cause of executive functioning issues?
> > >
> >
> > Yes, I think so, and I've noted a remarkable improvement of executive function after adding buprenorphine - the most potent kappa-antagonist in clinical use - to my regimen of methylphenidate and guanfacine.
> >
> > > (i want to try naltrexone, but i worry its lack of selectivity, and the fact that it is very old and concrete knowledge of it's carcinogenic potential is just not there, making the idea of long term use seem a bit creepy. sigh.)
> > >
> >
> > While I'm not particularly worried about its carcinogenic potential, I'm highly suspicious of its antagonism of mu-opioid receptors, as this may reduce dopamine release especially in the nucleus accumbens.
>
> i don't know how easily i could get a buprenorphine rx. it's the most potent kappa antagonist in clinical use? how low can you go and still have the ideal amount of kappa antagonism needed? what are it's other effects/affinities at a kappa-blocking dose?
>The ideal dose of buprenorphine is unclear, and I am in fact trying to determine it myself. I expect it to be in the range 0.3 to 4 mg a day.
> i figure i could at least try naltrexone,
Nalmefene may be an alternative to that.
> unless someone knows how to get nor-binaltorphimine...
>It's available from some chemical suppliers. Some of them may, for a number of reasons, not be willing to sell to individual consumers, and so are best approached in the name of an company or other organisation.
> i have to admit i know nothing about the mu receptor, or the NAc, or what cognitive or neuropsych functions depend on dopaminergic activity in the NAc (as opposed to the PFC.)
>It plays a major role in motivation and incentive, but also reinforcement, memory, desire, and many other functions and aspects of behaviour.
The shell of the NAc is regarded as the pleasure centre of the brain, and dopamine plays a major role in its neurochemistry, but dopamine does not really appear to be responsible for the feelings of pleasure and joy, but rather for the motivation, desire, anticipation, and drive to achieve these feelings.
Posted by iforgotmypassword on June 6, 2008, at 5:05:06
In reply to Re: 2006 article, posted by undopaminergic on June 4, 2008, at 4:11:14
or is it just a mu antagonist?
have i been under the wrong impression the whole time?
Posted by undopaminergic on June 6, 2008, at 8:03:28
In reply to wait, is naltrexone even a kappa antagonist?, posted by iforgotmypassword on June 6, 2008, at 5:05:06
> or is it just a mu antagonist?
>
> have i been under the wrong impression the whole time?
>It's my understanding that naltrexone is significantly more potent as a mu-antagonist, but that it is also a kappa-antagonist at clinically useful doses. However, I don't have any receptor affinity data at hand.
Posted by linkadge on June 11, 2008, at 9:00:34
In reply to Re: wait, is naltrexone even a kappa antagonist?, posted by undopaminergic on June 6, 2008, at 8:03:28
I've heard of salvia (a potent kappa receptor agonist) having both depressant and antidepressant properties.
Usually people report experiencing a mood depressing (or anxiety provoking effect) while smoking, but that the pleasuarable effect usually happens after this wears off.
I am thinking that the potent short acting kappa agonism of salvia may desensize the receptor in some way.
Linkadge
Posted by Crotale on June 20, 2008, at 1:22:46
In reply to Re: 2006 article, posted by undopaminergic on June 4, 2008, at 4:11:14
> The article about buprenorphine for refractory It's not really accurate. The DEA focus on doctors prescribing large quantities of controlled substances, and whom they suspect not to be following reguladepression can be found by following one of the links listed in the message at:
> http://www.dr-bob.org/babble/20080528/msgs/831995.htmlDr Bodkin, who was the chief author of the article in question, was the consultant who originally suggested I try buprenorphine. This was back around 1996 or 1997.
> Another document - an editorial - mostly regarding the reasons why buprenorphine isn't likely to become an FDA-approved treatment for depression, can be found at:
> http://web.archive.org/web/20031118092749/http://www.sciencething.org/Callaway.pdfDr. Callaway's editorial is very much worth reading.
> Mu-agonism has a range of effects - some of them may be highly desirable, while others may be neutral or troublesome. Some effects will be noted only initially, while certain others will persist throughout treatment. Start at a low dose and titrate according to effect and tolerability.
I recommend starting at 0.15mg t.i.d. or p.r.n., based on personal experience.
> It is extremely unlikely that the DEA would target someone who prescribes buprenorphine once in a while.
I agree with this.
> Is is very safe, and while there's a definite risk of physical dependence, addiction is not likely - unless you have a propensity for abusing drugs - e.g. dissolving and injecting tablets.
Physical dependence is quite mild, although you should not discontinue it abruptly because of the risk of rebound depression.
It's safe enough that I believe it's considered the treatment of choice for pregnant drug addicts, and I don't think there have been any deaths from overdose (except possibly in combination with OD of benzodiazepines).
Crotale
Posted by jrbecker76 on July 21, 2008, at 23:48:24
In reply to stress, dynorphin, kappa opioid receptors, posted by linkadge on May 28, 2008, at 11:04:07
> So apparently kappa opioid receptor agonism can cause depression by inhibiting the release of dopamine in the neucleus accumbens.
>
> Stress increases the levels of dynorphin in the neucleus accumbens which is a agonist at kappa opiod receptors.
>
> Buprenorphine is a fairly potent kappa antagonist.
>
> Exercise decreases dynorphin levels in the neucleus accumbens (antidepressant effect?)
> Also the TCA's appear to decrease dynorphin levels.
>
> Anyhow sounds like an interesting target for mood disorders. Anyone have any input?
>
> Linkadge
>
>p38 kinase ihibitors, currently in trials by a number of companies for COPD and other inflammatory disorders, inhibits kappa activity. In early animal testing, it showed strong inhibition of dysphoria. It is currently being explored as an antidepressant by GSK.
JB
Posted by Questionmark on August 7, 2008, at 0:47:04
In reply to Re: salvia and kappa receptors, posted by linkadge on June 11, 2008, at 9:00:34
Darn it, I just posted something in the kappa opioid thread above this one, but then saw that this thread would be more appropriate and relevant for it. So i'm posting it here too/instead. I hope that is alright.
...
Wikipedia (http://en.wikipedia.org/wiki/Kappa_opioid_receptor) states that the belief that kappa opioid receptor agonists are dysphoric is a misconception. I'm not sure. But if salvinorin A is the potent [and selective(?)] kappa opioid agonist it is accepted as being, then I am a bit skeptical that agonists of these receptors are exclusively dysphoric-- unless maybe you/they're referring to chronic activation over some extended periods (and not just acute activation). Because I know that while salvinorin A isn't by any means the most euphoric substance, and it seems like many people aren't particularly fond of its effects, there are many people (myself included) who do also enjoy its effects to some extent or another. And personally, although the very high dose, melt-into-the-world to become a cog-in-a-rapidly-spinning-mega-wheel can in certain ways be quite unpleasant, I have quite often been capable of enjoying lower doses. Anyway, the point of that rambling is that I think it may depend on... I don't know, other factors-- such as possibly, selectivity of the drug, potency and/or degree of kappa opioid receptor activation, etc.-- whether or not kappa receptor agonists are dysphoriogenic (sp.?). But again maybe it may simply be when receptor activation is sustained fairly frequently over a period of time (e.g., multiple days), and not just acute activation like I was talking about.
But in regard what Linkadge/you had to say...>
> Usually people report experiencing a mood depressing (or anxiety provoking effect) while smoking, but that the pleasuarable effect usually happens after this wears off.Yeah, I remember reading this too (though I don't think heard about it personally). Strange. And interesting.
> I am thinking that the potent short acting kappa agonism of salvia may desensize the receptor in some way.
You know I remember wondering about this same idea before, but I had forgotten about it. Yeah, that could totally be what's going on here with salvia. But then that doesn't explain why it is capable of producing immediate pleasant effects. Unless they're just unpleasant for many or with a high enough dose/activation. Eh, i dunno.
This is the end of the thread.
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