Discussion of Adenosine paper

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Rustsmith
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Discussion of Adenosine paper

Postby Rustsmith » Sat Feb 10, 2018 7:10 pm

The following was split from the "Dipyridamole" thread created by stjohnh to report on his experience trying Dipyridamole to treat his RLS based upon the information contained in the Adenosine paper http://bb.rls.org/viewtopic.php?f=5&t=4749&start=375 that was posted on January 12.



Holland, hope you got another good night's sleep.

I have been re-reading the paper because we are in the middle of a snowstorm today. There are 2 sentences on page 4 that may explain why dropping your dose back has helped. These say
Under basal conditions, adenosine tonically activates predominantly A1R, which inhibits glutamate release. A2AR is activated with higher concentrations of adenosine, which would normally occur upon strong glutamatergic input. Activation of A2AR negatively modulates A1R signaling in the heteromers and promotes the opposite, glutamate release.


Since hyperarousal is due to a hyperglutamatergic state, I read that to say that increasing adenosine triggers A1R and lowers glutamate. But too much adeonsine triggers A2AR, which releases glutamate and therefore returns the hyperarousal state. If that is correct, there will be a sweet spot with dosing and ENT1 agonist. You need enough to reduce dopamine and glutamate levels, but not so much that it triggers A2AR and returns the hyperglutamate condition.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

stjohnh
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Discussion of Adenosine paper

Postby stjohnh » Sat Feb 10, 2018 9:15 pm

Steve, read Beth's post from February 7th, and tell me if that all fits together. It's only been the last 36 hours that my sleeping has improved enough so that I can even start to think about rereading the article. I have several other things that I am obligated to do before I can do that.

The last two nights I have been taking 112.5 milligrams dipyridamole and 0.0625 mg pramipexole. Are you suggesting I drop the pramipexole and take dipyridamole only at either a slightly higher or lower dose?

I have been starting to think that there may not be a dose of dipyridamole will get the adenosine levels at the needed amount to both take care of the hyper dopaminergic problem and the hyperglutaminergic problem.
Last edited by stjohnh on Sat Feb 10, 2018 9:21 pm, edited 1 time in total.
Blessings,
Holland

badnights
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Re: Dipyridamole

Postby badnights » Sat Feb 10, 2018 9:18 pm

Steve, you said that more clearly than I managed to, even though I said it in two consecutive posts (Feb 07, 2018 12:37 am just after midnight, and then again at 10:53 am).

Holland wrote: it is possible that the improvement in sleep that the responders noticed was due to reduction in urge to move symptoms, and not due to the primary sleep disturbance that people with more severe RLS have. In other words, primarily dopamine path effects rather than glutamate path effects
I have wondered about this. I do remember arousals at night without the WED symptoms, prior to beginning any treatment, but the strong hyperarousal problem didn't happen until after I started hydromorphone. (I had been on codeine before that, but I don't know if my hyperarousal was bad then, because my symptoms were so godawful I couldn't tell.) Either the progressing disease or the use of opioids precipitated the strong hyperarousal.

First question: do we have any members or do we know of anyone who has the hyperarousal problem in a severe way (sleeping aid of some kind required) who does not take opioid meds?

Second, a thought not a question, this might be a productive avenue of research, if opioids cause the severe hyperarousal - what is the mechanism of interaction between opioid and glutamate systems? And even if opioids don't cause the severe hyperarousal,

... I lost my thought.
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

Rustsmith
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Discussion of Adenosine paper

Postby Rustsmith » Sat Feb 10, 2018 9:29 pm

Beth, I agree that we were referencing the same thing, just different places in the paper.

Holland, I am not suggesting any changes at this time. My point is that this part of the paper explains why you are doing better now on the lower dose. The movement part is still controlled, but the hyperarousal is probably down because your A2ARs aren't dumping glutamate, or at least less.

Finally, I agree that this opens the question about opioid hyperarousal and glutamate levels. It is may even be something that is covered in our of our multitude of earlier references. With what this paper has taught us about heteromers, there may even be a similar link between the mu-opioid receptors and glutamate that is similar to the A2AR ones.

EDIT: I did a search and found a lot of info about opioids, glutamate and GABA. However, I didn't find anything that directly addressed this, at least not that I could understand in a quick scan. With all of the relevant research on addiction, withdrawal, etc. I feel confident that this info is out there, but I could not find it quickly.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

stjohnh
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Re: Dipyridamole

Postby stjohnh » Sun Feb 11, 2018 3:25 pm

badnights wrote:...the strong hyperarousal problem didn't happen until after I started hydromorphone. (I had been on codeine before that, but I don't know if my hyperarousal was bad then, because my symptoms were so godawful I couldn't tell.) Either the progressing disease or the use of opioids precipitated the strong hyperarousal.

First question: do we have any members or do we know of anyone who has the hyperarousal problem in a severe way (sleeping aid of some kind required) who does not take opioid meds?

Second, a thought not a question, this might be a productive avenue of research, if opioids cause the severe hyperarousal - what is the mechanism of interaction between opioid and glutamate system...


I don't have any personal experience that I know of regarding arousal from narcotics. The closest experience I had occurred a couple of years ago when I had a complex ankle fracture requiring a surgical correction and I took Percocet every day for a couple of weeks. Of course I had no RLS during that spell. I don't remember if my RLS symptoms worsened after stopping the Percocet. I don't particularly remember any sleeping difficulties, but I don't remember much at all during that spell. Does anyone know if the hyperarousal that occurs from an opioid is some effect on the glutamatergic system or some other opioid effect? Do people that take opioids for reasons other than RLS have hyperarousal as well?
Blessings,
Holland

Rustsmith
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Discussion of Adenosine paper

Postby Rustsmith » Sun Feb 11, 2018 7:01 pm

I haven't been able to find much literature that connects opioids and hyperarousal. That doesn't mean that it isn't there, but it might be too old and well established to get hits from the search engines that I tried using.

Insomnia and sleep problems are listed as a side effect for opioids, but that was about it. So I guess it raises the question of whether the opioid causes the hyperarousal for us or it the opioid just treats the movement issues and leaves us with hyperglutamate induced insomnia because the opioid only treats the hyperdopamine side of RLS.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

badnights
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Discussion of Adenosine paper

Postby badnights » Sun Feb 11, 2018 7:08 pm

I have the impression that hyperarousal from opioids does not affect pain patients, for two admittedly imperfect reasons: I haven't seen hyperarousal listed as an opioid side effect on the usual sites, and my GP's clinical experience is that it causes drowsiness. At first I thought opioid-induced hyperarousal only affected a few WED patients, like me and Ann. But then a lot of other members here started to mention it, and I realized it was common - though not ubiquitous - among WED patients.

So I'm still unsure if it ever happens among pain patients.

And I have lost my library access (temporarily) so for now, I can't help in the search for a link between the opiate and glutamate systems. It will take a lot of digging, I think, to find a relevant link, given that we're all outside our fields of expertise. We risk barking up the wrong tree (or, as the saying goes, knowing just enough to be dangerous).
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

Rustsmith
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Discussion of Adenosine paper

Postby Rustsmith » Sun Feb 11, 2018 7:42 pm

Beth, I totally agree with your barking comment. I found quite a bit about hyperarousal with PTSD. It appeared that there was a link because the spoke about it occurring with patients were self medicating. But I quickly realized that I wasn't comfortable with the connections that MIGHT have been there. 1) was hyperarousal referring to sleep or emotions and 2) self medicating with what?
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

stjohnh
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Re: Discussion of Adenosine paper

Postby stjohnh » Mon Feb 12, 2018 7:04 pm

Here's a question that's been bothering me about the adenosine paper. The very first sentence says "the symptomatology of restless leg syndrome includes periodic leg movements during sleep PLMS, dysesthesias, and hyperarousal." During the rest of the paper there are frequent references to PLMS but very few references to urge to move (a type of dysesthesia). But urge to move symptoms are amongst the most important part of the diagnostic criteria generally used for restless leg syndrome. And indeed, PLMS is not at all mentioned in the usual diagnostic criteria. I don't understand that.

At the top of page 3 is a reference to urge to move, but the sentence structure makes it unclear whether they are equating urge to move symptoms and PLMS or not.
Blessings,
Holland

stjohnh
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Re: Discussion of Adenosine paper

Postby stjohnh » Mon Feb 12, 2018 7:47 pm

This is a helpful article for those interested in how adenosine works in the sleep cycle.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769007/
Blessings,
Holland

Rustsmith
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Re: Discussion of Adenosine paper

Postby Rustsmith » Mon Feb 12, 2018 8:34 pm

Holland, I'm not sure about the urge to move vs PLMS issue. But in the recent paper where they did the genome wide survey that identified something like 14 new RLS genes, they made a comment about PLMS being a genetic subset of RLS. MAYBE that is what the authors were considering, i.e. PLMS is related to the urge to move side of RLS. Granted, that is a reach for an explanation, but it is the best I can come up with right now.
Steve

Augmentation Evaluation http://bb.rls.org/viewtopic.php?f=4&t=9005

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

badnights
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Re: Discussion of Adenosine paper

Postby badnights » Sun Feb 18, 2018 7:52 am

Re PLMS, that bothered me too. The presence of PLMs is not a diagnostic criterion and PLMS is not present in all WED/RLS patients. Since PLMS is quite common in WED/RLS, I guess we can't shoot them down for saying it's part of the RLS symptomalogy, but what they say in the first sentence of the abstract that you quoted, and in the first paragraph (after the abstract), is plain wrong. They say RLS symptoms include a "periodic .... urge to move the legs or periodic leg movements during sleep (PLMS) and hyperarousal". The urge to move is not periodic. And it is not exchangeable with PLMS in diagnosis. There may or may not be PLMS, but there is always an urge to move - if not, then it's not RLS/WED. (On the bright side, I was delighted to see the hyperarousal being acknowledged and elevated to the status of a symptom.)

I think that maybe these guys working with mouse bits and chemicals are pretty far removed from patient encounters, and have no clinical experience. Their only source of information on WED/RLS is what they read in papers. Perhaps a lack of rigorous reading, a failure to properly imagine what they're reading, has led to their misunderstanding of what the symptoms of WED/RLS actually are. And now they're propagating the misunderstanding. Sigh.

On page 3, they're implying that their mouse model would be better if it had PLMS as well as RLS-like behavior. Again, not really true. They should be clearly separating these two things.
Beth - Wishing you all restful sleep tonight
WED/RLS AUGMENTATION:
viewtopic.php?f=5&t=6532&p=61601#p61601
Discussion Board Moderator's posts don't reflect the RLS Foundation's opinion & are not medical advice

stjohnh
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Re: Discussion of Adenosine paper

Postby stjohnh » Sun Feb 18, 2018 6:45 pm

I do understand that it's very difficult to get an animal model for urge to move symptoms. However, some of the authors are among the best known RLS researchers. I have a hard time believing that they really don't understand that urge to move is different than PLMS.
Blessings,
Holland


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