22 replies to this topic

[Vieno]

I suffer from a brain disease that apparently nobody else but me and to a less severe extent my brother have. I'm in the process of figuring out what is the pathogenesis and how to treat it and I hope you could give me some ideas. My case has been discussed in my previous thread (http://www.longecity...hedonia-thread/), but it eventually became clear that my disorder is unlike that of anyone else's and must not be described as "anhedonia", therefore making that thread and many of its posts obsolete.

What I suffer from is technically called "consummatory anhedonia" (http://www.ncbi.nlm....pubmed/20603146), and more specifically, of the "objective" type. Consummatory anhedonia (CA) means inability to experience pleasure when stimulated with normally pleasurable stimuli such as music, sugar or sex. This differs from depression etc. in the sense that all my emotions as well as motivation are intact, it is only the pleasure that is gone - and the pleasure is fully gone. To give you an example, if I have sex everything else is completely normal - the arousal, the lust, the motivation, the excitement, the zest - but the act fails to "lift me up" so to speak, and this is especially obvious in the case of orgasm which makes me feel nothing. Noteworthily, recreational drugs such as methamphetamine, opium and cannabis fail to induce pleasure in me as well (ie zero euphoria). In my case this CA is objective (OCA) in the sense that instead of me only having some difficulty subjectively experiencing the pleasure, it seems that the pleasure is fundamentally not being generated at all: I, just like my brother, have very lacking reaction to opioids such as morphine suggesting a fundamental dysfunction of the opioid system. I do not react in any way even at high doses, and my brother has a minimal reaction. Even though considering endorphins simply as the direct source of pleasure is a simplified and outdated view, evidence points to the opioid system and specifically the mu receptor in general being at the centre of pleasure generation (http://tinyurl.com/ohcxpz4). Another hallmark feature of this disease is our lack of reaction to GABA-B agonists (GHB and phenibut), suggesting that the opioid and pleasure dysfunction might be (but surely is not necessarily) GABA mediated. GABA has been found to play a profound role in pleasure regulation in rodents.

There are some other symptoms that might be related, mainly concerning sleep, general stimulation and circadian rhythm which is out of order in an odd way, but they are less pronounced than the CA. Some research on mice links these other symptoms to hypofunctional GABA-B.

I have now suffered from this for years (2,5 years at "full blown" scale to be precise) and have been trying to find the cure for a rough year. As my previous thread indicates, I've gone through very extensive exprimentation with various drugs. I tried all the recreational drugs and then more sophisticated alternatives based on various theories. Nothing has helped and its beginning to look like direct neuromodulation might not be the answer. To me restoring GABA-B function via drugs still seems like a potential cure, but I think the answer might lie somewhere else as well. I am soon going to get CT/MRI scans to see if there are any structural anomalies (like a tumor) as well as complete blood analysis for minerals and metals to see if anything is out of the ordinary. But obviously, the truth may still remain unknown after these. So what else could I do?

Basically, I have two major questions.

1. What tests/examinations could I get done that could potentially reveal something about the pathology? What types of brain scans and in what setting (rest, under the influence of a drug, engaging in normally pleasurable activities..)? What should blood/urine/hair be tested for? Can EEG reveal something? Any reason to try to get neurotransmitter quantities evaluated? What else?

2. What types of brain dysfunction could theoretically be the cause of my condition? Erroneous neurochemical signalling, neurodegeneration, tumor, metal poisoning? What else?

To be clear, I made this thread for the purpose of developing general ideas about what kind of a disorder we may be dealing with and what avenues should I follow to gain more insight. Discussion about what receptors exactly need to be modulated in what way exactly is another topic and I deliberately didn't go into that here, if you wish to discuss that perhaps PM me, I do want to hear your ideas. Also feel free to inquire about the specifics of the symptoms, tested drugs, theories, findings etc.

Thank you!

Edited by Vieno, 24 October 2013 - 10:20 AM.

[Eruditus]

What that makes absolutely no sense to me. How can you still be motivated without the pleasure reward, this alone would send most people into a depression; pleasure is what signals my motivation. None the less you are right that there most be some neurological function inhibited, however as to what that function is I think you are taking stabs in the dark here.

Could be dopamine, could be enorphines and could be gaba but more likely its a conjunction of all these systems working together. Pleasure is not one key sensation that all people experience at a universal level. Like you said when you indicated your condition being unique, but so is the experience of pleasure. I can experience pleasure but most of the time I cannot bring about the motivation to chase after that pleasure.

In any case this seems a very bizar biological scenario to me. Do you not think there may be a possibility of subconscious repression of pleasure? A more Freudian approach yet it may be worth looking into with a qualified hypnotherapist. In any case good luck on figuring this one out :o

Edited by Eruditus, 24 October 2013 - 10:52 AM.

[Vieno]

My case has been discussed extensively here and on other forums as well as with doctors so I do know what I'm talking about. I've spent over a year doing nothing but researching this. I am a layman in terms of brain function but I have became an expert on all things pleasure. I do not have motivation for pleasurable activities anymore as I know they won't be pleasurable, but the motivation itself is not damaged. I have strong motivation for finding a cure, for example, and promising ideas excite me. It's the pleasure system that is dysfunctional. My condition can send me into depression, but is not itself depression. And this can't be psychological as I do not react to opioids.

I'm not expecting to find a definitive answer here, I'm only looking for new avenues to follow.

Edited by Vieno, 24 October 2013 - 11:24 AM.

[xks201]

Sounds like opiate or hormone deficiency.

[tunt01]

Seems pretty unusual. Must be something related to how your striatal dopamine is being hijacked or something related. Do you have motivation to avoid pain or suffering? The motivation system has two segments 1) reward (striatal dopamine) and 2) avoidance of pain/risk/consequences (insular dopamine).

[Tom_]

You may disagree entirely but this still sounds like depression to me - just with an atypical presentation (not atypical depression (a sub-type)).

Personally I think an MRI/brain scans are simply wasting your money but that is your business not mine.

Even if you don't think its depression its worth ruling out and if its not the causative factor then its quite possibly co-morbid. Further more even if depression has nothing to do with it they might bring about some symptomatic relief.

Diagnosis by treatment IMO is worth it in this case. Set yourself x amount of weeks to go through a depression drug algorithm and if possible supplement it with CBT (which is worth trying in any case for symptom management even if its got nothing to do with a neuropsychiatric disorder).

Sarting with an SSRI isn't the best option for you I don't think.

Mirtazapine or Duloxetine/Milnacipran would be where I'd start. Increase to maximum tolerated dose by week four and if there is no improvement by week 6 move to stage two.
If there is a partial response combine the above two (to create Californian rocket fuel) or add T3 and wait a further 4-6 weeks.
stage 2
trial Nortriptyline or Amitriptyline (used for some neurological disorders anyway) for 6 weeks or Moclobremide (requires 1 week off the above drugs).
if there is a partial response add in T3, low dose atypical antipsychotics or another antidepressant
stage 3
try a full MAOI for 4-6 weeks.

There is no reason you can't carry on with other tests and in some cases other treatments.

One of the most important thing you can do is stop using the drugs of abuse.

[lammas2]

I suffer from a brain disease that apparently nobody else but me and to a less severe extent my brother have. ... /---/ ... I have now suffered from this for years (2,5 years at "full blown" scale to be precise) ...

Don't you think there might be something to this? You and your brother seem to be the only people with this kind of problem. Also, since you weren't born with this, don't you think that this was caused by a highly stressful event (or period) in your family's life? Try to remember when this started and what kind of problems you two were going trough at the time. Death of a loved one, domestic violence, bullying...? Maybe finding the hidden root cause and treating it accordingly can provide relief. I'm not saying that it is definately a psychological problem, but I really reccommend you to take a good look on your past.

[scitris]

Are you sure that they are the only symptoms you have? i dont mean necessarily other cognitive/mental manifestions. Maybe you have overlooked some differences.
changes in skin, hair, unusual weight gain/loss, digestive issues, vision, everything could be relevant. More information would lead to a more precise conclusion.

One thing i can tell you, you are not alone with a unique symptom-complex and everything has a solution. But i see that you arent stupid and so i think you think similiar, why otherwise you would be still searching for a solution? why would you still be excited about new ideas, theories, informations that you think are relevant for you? Maybe there is one thing which induces pleasure in you, maybe that ideas, theories and informations i was speaking of?!
Learning about things that you think are relevant in one way or another.

So now its your turn.

[Anagram 3.3]

Hey I am in the same wagon as you Vieno, I cannot experience pleasure in a way sort of similar to what you described.
Unlike the very peculiar condition and response you have to GABA, I cannot perplexingly cannot experience serotonin mediated effects similarly.
In fact I have taken illegal drugs like LSD, and experienced little to nothing on my mood.

[Keynes]

Interesting. Some more background info regarding your family history would be helpful, like if some specific event took place 2,5 years ago in your family and how similar your brothers condition is to yours. Age is also relevant (for both of you). Other symptoms etc.

Hypothesis:
Since both of you have the condition, it's genetic. You both share the same gene mutation that affects these pathways (ie through a gene encoding a receptor or an enzyme involved in the neurotransmitter metabolization). You could do a DNA test at for instance 23andme to check for mutations. You could also do a lumbar punction to check for abnormal levels of metabolites (con: rather unpleasant procedure).

http://www.pndassoc.org/pdf/Hyland.pdf

Disorders of dopamine & serotonin metabolism are treatable conditions
• Disorders of dopamine and serotonin metabolism are treatable to varying degrees.
• Disorders of tetrahydrobiopterin metabolism are treated with mixtures of a low phenylalanine diet, tetrahydrobiopterin, Sinemet (L-dopa/carbidopa), 5-hyroxytryptophan, monoamine oxidase inhibitors and folinic acid, depending on the particular disorder.
• Tyrosine hydroxylase deficiency is treated with Sinemet.
•Aromatic L-amino acid decarboxylase deficiency is treated with monoamine oxidase inhibitors, vitamin B6 and dopamine agonists.
• Dopamine β-hydroxylase is treated with dihydroxyphenylserine.

[Vieno]

I think I made a mistake not sharing my whole story and omitting so many details. It was stupid of me to assume that a description as short as what I gave in the OP could give you a picture clear enough of the nature of my condition. Once you get to learn the details of my case, you will have no doubt that this is 100% non-psychological as well as indeed a unique case. I'll write a detailed report and perhaps get a mod edit it into the OP?

Interesting. Some more background info regarding your family history would be helpful, like if some specific event took place 2,5 years ago in your family and how similar your brothers condition is to yours. Age is also relevant (for both of you). Other symptoms etc.

Hypothesis:
Since both of you have the condition, it's genetic. You both share the same gene mutation that affects these pathways (ie through a gene encoding a receptor or an enzyme involved in the neurotransmitter metabolization). You could do a DNA test at for instance 23andme to check for mutations. You could also do a lumbar punction to check for abnormal levels of metabolites (con: rather unpleasant procedure).

http://www.pndassoc.org/pdf/Hyland.pdf

Disorders of dopamine & serotonin metabolism are treatable conditions
• Disorders of dopamine and serotonin metabolism are treatable to varying degrees.
• Disorders of tetrahydrobiopterin metabolism are treated with mixtures of a low phenylalanine diet, tetrahydrobiopterin, Sinemet (L-dopa/carbidopa), 5-hyroxytryptophan, monoamine oxidase inhibitors and folinic acid, depending on the particular disorder.
• Tyrosine hydroxylase deficiency is treated with Sinemet.
•Aromatic L-amino acid decarboxylase deficiency is treated with monoamine oxidase inhibitors, vitamin B6 and dopamine agonists.
• Dopamine β-hydroxylase is treated with dihydroxyphenylserine.

This is what I'm talking about! Novel ideas. That 23andme looks interesting. How can it check for mutation relevant to my case? I don't really understand how it works.

Dopamine and serotonin are not central in my disease as I have thoroughly modulated them with drugs and gotten normal responses but no impact on pleasure. Do you know if CSF analysis can provide info on other neurotransmitters/neuromodulators?

I'll provide more details of my case soon.

[Vieno]

Over three years ago I started to notice that things that had used to touch me very strongly, so strongly that I described them euphoric, were not working as well anymore. I mostly noticed this with things like music, films and literature. As time passed, I began to experience this more and more, and noticed that this inexplicable deficit in this specific feeling extended to everything: I found no reason to consume sugary foods or any form of art or entertainment anymore. As a young man I had a need for sexual stimulation, but it had became pleasureless. Around 2,5 years ago this had became so absolute, that I simply quit all these activities. I didn't eat candy anymore, I didn't listen to music anymore. But otherwise I felt normal. I was normally emotional. I could find enjoyment in, for example, the abolition of various pains such as hunger, thirst, fatiguer or surely even pain itself, and I could find excitement and enthusiasm in good things upcoming. I thought that the lost feeling would return one day and thus wasn't generally feeling too low. But 1,5 years ago I got sick of this and wanted a change. I went to a psychiatrist and told her about my problem. I explained that things previously so meaningful to me had became empty. I then saw her and a psychologist multiple times over a couple of months, until they declared me mentally healthy. There was no observable problems in my thinking, mood or emotions. They said they don't know what is wrong with me.

I started to study the matter on my own and concluded that it is specifically pleasure that is gone. Other feelings - emotions - were intact. I discussed my case extensively on many forums such as this one, and many theories were developed. I tested numerous drugs, and found out that:

I have zero reaction to opioids (morphine, codeine) and my brother has minimal reaction
I have very little reaction to GABA-B agonists (phenibut/GHB) and so does my brother
Other recreational drugs provide normal effects except for the pleasure that simply doesn't occur (with the exception of low-level pleasure occurring with large doses of stimulants like methamphetamine, methylphenidate and methiopropamine)

While discussing on the forums, I found out that this syndrome of OCA without emotional deficit had occurred a couple of times in GABA-B agonist abusers. One abuser of phenibut, one of GHB and one of GBL had all developed complete CA for a while, and the GHB/GBL users had tested drugs while in the WD and found opioids to have no effects - suggesting the CA is objective in nature - and stimulants to be void of pleasure. Considering how I lack reaction to GABA-B agonists, it seems like there is a link between GABA-B hypofunction and OCA.

The CA is not my only symptom however. Around the same time that I observed CA for the first time, I noticed that this white sticky substance was accumulating to my hair and that I couldn't sleep well at nights - I felt hot and alert. I saw hairdressers and a doctor but they found the skin of my head normal. I later noticed that my skin throughout my body was getting oily and sticky, and that in order to keep it in normal condition I have to peel it off a couple of times a week. My sleep issues got more severe, every night I feel very hot and alert and I'm unable to fall asleep until morning. Lowering the room temperature helps but is not a perfect solution. I later found a link between my skin issue and the sleep issue. Apparently chronic methamphetamine users develop a skin similar to mine, and this is speculated to be due to increased (surface) temperature. I'm hot every night - this causes my skin to get all oily and loosy. Interestingly, the only somewhat useful sleep aid for me is an antipsychotic (perphenazine). Aside from being an antihistamine, it's a potent antidopaminergic, and it could very well be that my circadian/sleep issues are due to hyperdopaminergia. The symptoms described in this study match to me perfectly, and suggest another link to GABA-B hypofunction: http://onlinelibrary...006.03806.x/pdf

I am 20 years old and my brother is 22. I started to experience the symptoms at the age of 17, he both CA and loss of opioid effects around the age of 20. For him the sleep issues are far less severe, and the CA seems a bit less severe too, especially considering how he does have some reaction to opioids.

Now, what exactly causes this GABA-B hypofunction is a valid question, but has proven to be extremely difficult to answer. So I made this thread to come up with new avenues to follow, such as what examinations and tests should be undertaken. Thank you.

[Vieno]

Seems pretty unusual. Must be something related to how your striatal dopamine is being hijacked or something related. Do you have motivation to avoid pain or suffering? The motivation system has two segments 1) reward (striatal dopamine) and 2) avoidance of pain/risk/consequences (insular dopamine).

Dopamine doesn't have anything to do with pleasure, proved million times. I most certainly have all kind of motivation.

Are you sure that they are the only symptoms you have? i dont mean necessarily other cognitive/mental manifestions. Maybe you have overlooked some differences.
changes in skin, hair, unusual weight gain/loss, digestive issues, vision, everything could be relevant. More information would lead to a more precise conclusion.

One thing i can tell you, you are not alone with a unique symptom-complex and everything has a solution. But i see that you arent stupid and so i think you think similiar, why otherwise you would be still searching for a solution? why would you still be excited about new ideas, theories, informations that you think are relevant for you? Maybe there is one thing which induces pleasure in you, maybe that ideas, theories and informations i was speaking of?!
Learning about things that you think are relevant in one way or another.

So now its your turn.

I provided more details about the sleep/circadian issues in my previous post.

My emotions are intact and exploring promising avenues offers a lot of hope and comfort. It is enjoyable in a way, but the specific feeling of pleasure is gone. Not many people know this, but I've came to understand that pleasure is specific feeling separate from emotions.

Hey I am in the same wagon as you Vieno, I cannot experience pleasure in a way sort of similar to what you described.
Unlike the very peculiar condition and response you have to GABA, I cannot perplexingly cannot experience serotonin mediated effects similarly.
In fact I have taken illegal drugs like LSD, and experienced little to nothing on my mood.

What you have seems to be a serotonergic disorder. You don't really have emotions either, right? Chronic MDMA/SSRI use can cause that condition. Anyway, regardless of whether your condition was endogenous or caused by substance use, it has a different pathogenesis to mine. Check this out: http://mindandmuscle...-ssri-anhedonia

[Tom_]

My first bet is still a neuropsychiatric disorder (mental illness). And second in my list is a Major depressive disorder secondary to a primary sleep disorder.

You didn't mention it but if you've had a bump on the head then this could be a post-traumatic brain injury syndrome.

Trialing opioids, amefatmines, GHB etc without clear reason to (and I don't consider clear reason to be for diagnosis) has got to stop. You could be making what ever 'it' is worse or you could just be doing yourself damage.

You should have a comprehensive work up (I hope I mentioned that), if you haven't already. Including a physical exam (blood pressure, heart rate, basic reflexes and a look at your skin/hair) & bloods drawn (Basic metabolic panel, TFT's, LFTs, B12, F/CBC & C reactive protein, fasting glucose and anything else the physical exam indicates).

Here is a list of everything else I can think of that could possibly be cause your symptoms (none of them are likely, very few fit well at all but its the best I can do). A * is placed by any of particular interest. Some of them are syndromes which would require further investigation to find the actual cause and some of them aren't. In no order:

Predromal schizophrenia (its a hard disorder to classify and until frank psychosis or grossly abnormal behavior presents its difficult to do much about). I've left this by itself as its more likely than most of the rest but not something I'd actually suggest as a reasonable possibility.

Hyperthyroidism* - this is the only disorder I think warrants reasonable attention.
Cushing's syndrome/Hypercortisolism*
Chronic fatigue syndrome*
Hypothyroidism
Hypocortisolism
Infectious Mononucleous
Systemic lupus erythematosus
Multiple scerosis
Lyme disease
Syphilis - neurosyphilis (you would have had to have contracted it a while ago).
Coeliac disease
Early and mild Pellagra
Sub-clinical lead poisoning
extrapulmonry TB
HIV
Toxoplasmosis
Anemia
Fructose malabsorption
Graves disease (one of the primary dieaseases causing hyperthryoidism)
hypoparathyroidism
hyperparathyroidism
B 6, 9 or 12 defiency.

That is pretty much every non-psychiatric disorder I can think of with any relevence.

[Vieno]

Just going to repeat a couple of things.

No reaction to morphine/codeine (no analgesia, no euphoria, no sedation, no respiratory depression, no miosis, no constipation, no itch)

Emotions completely intact (joy, sorrow, excitement, anger, compassion, confusion, envy, you name it)

Here is a list of everything else I can think of that could possibly be cause your symptoms

Will go through these. Going to have vitamins B9/12 checked out soon. Thyroid levels are normal.

Edited by Vieno, 26 October 2013 - 06:42 PM.

[Tom_]

I forgot to mention - Wilson's disease, hepatitis, cirrhosis and any other disease that can cause hepatic encephalitis.

Paraneoplastic syndrome - plenty of cancers can cause Paraneoplastic syndrome although not so many that would cause neurological deficits.

[Mind_Paralysis]

Whatever happened to this? Did the OP ever find out what ailed him? A very curious case, I must say.

 

I would have assumed that it would be obvious that since the OP doesn't respond to anything opioid, that it would be prudent to check for polymorphisms to his opioid-system - perhaps he has a degenerative disease which affects the opioid-receptors? Similar to how Parkinsons causes degeneration of dopamine-receptors, you have a disease which degenerates your opioid-receptors.

 

If so, then the damage is quite possibly extreme already - damn near irreversible with current tech.

 

Only some of the juiciest neurogenics would then be able to help... *rubs hands like Gargamel from 'the Smurfs'*

 

The fact that you don't seem to be completely fearless nor depressed either however, suggests that the problem lies with the Delta-receptors - the same which causes the pleasurable response to a number of drugs.

 

The Mu-receptors are the ones which seem to play a role in depression, and hence agonism of delta has an antidepressant effect. Kappa-receptors are involved in PUNISHMENT instead of  pleasure, and without them, you become utterly fearless, possibly utterly immoral as well, since you would lack fear of ANY form of punishment - any form of negative outcome.

 

So you don't have problems with either MOR or KOR - that leaves DOR - which your response to opioids seems to imply.

 

 

So... any suggestions gentlemen? What parts of the brain have the most Delta-receptors? Perhaps we can find a neurogenic drug which shows mostly effect in that region? The OP could then utilize intra-neural injection - extreme, yes, but extreme diseases call for extreme measures - and expose his brain DIRECTLY to that drug...! The effects should be apparent within hours.

 

Any potential damage from the injection can be counteracted with other post-procedure neurogenic drugs. (I'm thinking a combo of NSI-189 and Dihexa - if that doesn't heal the damage, then my name is EARL!)

[Galaxyshock]

I've been in contact with Vieno and yes, he's still suffering from this extreme condition.

 

So you don't have problems with either MOR or KOR - that leaves DOR - which your response to opioids seems to imply.

 

 

I think you made mistake leading to this conclusion. MOR is the reward receptor, shown in studies to create sensory pleasure in its fundamental form. Whereas DOR is implicated in mood regulation.

 

Medievil has done extensive research to pleasure system and according to his postings the most important receptors, all interconnected, are:

- 5-HT2A

- Dopamine D1

- GABA-B

- Mu-opioid

 

Vieno has no response to agonism of any of these receptors when it comes to pleasure, except D1 with high dose stimulants. We're now looking at if there is a missing link that would be the potential cure. Metabotropic glutamate receptors show some potential to possibly have something to do with the reward system but no conclusions have been made. mGluR5 negative allosteric modulation did not produce any effect.

 

Anyone with any ideas feel free to chime in.

[Mind_Paralysis]

It's time to go epigenetic.

 

What are the genes related to MOR? I figure we start by having a look at compounds that cause upregulation of those genes.

 

Oh, wait, I just found it:

 

OPRM1 opioid receptor mu 1 [ Homo sapiens (human) ]

https://www.ncbi.nlm.nih.gov/gene/4988

 

Has Vieno done some genetic testing? I know 23andme actually provides data about this gene, which Promethease then deciphers - perhaps we can use that data to see if he has some unusual polymorphism?

 

He seems to be the complete and utter opposite of an addict, so we can already rule out any of those variations.

 

 

My brain is currently too mushy to examine these studies more closely, but a cursory glance makes me think there is some data in here which we can use to find out transcription-factors or something, of the Mu-opioid gene.

 

Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse.

https://www.ncbi.nlm...pubmed/26633001

 

Morphine-induced MOR-1X and ASF/SF2 Expressions Are Independent of Transcriptional Regulation: Implications for MOR-1X Signaling.

https://www.ncbi.nlm...pubmed/26553431

 

 

Association between human mu-opioid receptor gene polymorphism, pain tolerance, and opioid addiction.

https://www.ncbi.nlm...pubmed/12898579

 

 

 

And here's a little bit of a different idea about what's wrong with him - have you considered a gut-brain circuit? There are multiple genes, more than for other diseases, indicating a link between HEAVY addiction disorder and Autism - opioid-system abnormalities are implicated in both.

This study, shows that apparently there's a system wherein the gut heavily MODULATES THE MOR'S(!).

 

Mu-Opioid Receptors and Dietary Protein Stimulate a Gut-Brain Neural Circuitry Limiting Food Intake

http://www.cell.com/...0X?showall=true

 

Could Vieno, in essence, have MEGA anti-autism?? I.e, something is wrong with his gut, and it keeps modulating his MOR's down, down, down... Instead of up, up, up, as in the case of addicts.

 

 

And finally, when digging through this stuff, I found something interesting... this quote:

 

"It is thus intriguing that Gpm6a has been found to stimulate endocytosis of μ-opioid receptors from the surface of neuronal cells"

 

Found in this study:

A single gene defect causing claustrophobia

http://www.nature.co.../tp201328a.html

 

 

Which leads to these two studies:

Post-transcriptional regulation of mouse mu opioid receptor (MOR1) via its 3' untranslated region: a role for microRNA23b.

https://www.ncbi.nlm...act&holding=npg

 

Membrane glycoprotein M6B interacts with the human serotonin transporter.

https://www.ncbi.nlm...act&holding=npg

 

 

Endocytosis... glycoprotein... are these further implications of the digestive and metabolic systems modulating the MOR? Apparently Endocytosis is the process through which cells take in various substances, and glycoproteins seem to have something to do with this process as well... hmm...

 

 

Trying to think if we can find some kind of epigenetic super-food Vieno can eat! Which would then make him feel stuff again. Hmm...

 

 

 

[Galaxyshock]

Interesting contribution. I had been thinking about epigenetics in the past. The absolute consummatory anhedonia Vieno suffers from started first occuring in his late teens and so did his brother's but to a lesser extent. This indicates that there is a genetic predisposition. But why, exactly at certain age, did this occur. The brain isn't fully developed until around 25 if I'm correct, so are there be some specific brain parts developing at late teens that could cause this what appears to be a shut-down of hedonic hotspots in the brain. Now to track down the epigenetic changes is, well, something that would require some extensive knowledge of the area.

 

Before a full-blown condition he did experience "windows" where pleasure would occur normally again. This indicates us that it isn't neurodegenerative condition like you suspected earlier. I'm not sure about the gut-brain connection in his situation. He doesn't seem to be suffering from any abnormalities in the gut but of course there are possibilities, the gut is called a "second brain" for a reason. He trialed Proglumide which is a cholecystokinin antagonist and known to reverse opioid tolerance but it did nothing. I don't think there's a super food in the world that would cure this condition, but I did suggest him to try fasting once. He thought it to be quite radical but I think when the times are desperate this could be worth a trial. Another idea would be to go on ketosis and see how his brain runs on ketones.

 

To different approach, I don't think it was mentioned in this thread but there are a few anecdotal reports over the internet of similar condition to Vieno's occuring in withdrawal from GHB and one from Phenibut. That is, pure consummatory anhedonia (CA) and immunity to opiates. I'm the one who abused Phenibut and ended up with CA lasting several months but eventually it resolved itself. I did not try opiates though but alcohol which reward depends on endogenous opiates didn't induce pleasure and neither did any natural one's like orgasm. One GHB abuser on Bluelight developed CA lasting years, which didn't respond to any single recreational drug except some mild benefit from Ketamine if I remember correctly. I think he mentioned several years after the withdrawal that when it comes to pleasure "something never came back". Then there's Medievil who is immune to opiates and suffers from extreme anhedonia, but stimulants fix him and make opiates work. GHB and Phenibut are both GABA-B agonists. Vieno doesn't respond to GABA-B agonism at all, and he has similar symptoms that occur in GABA-B1 receptor knock-out mice. I suspect similar epigenetic changes occuring in sudden withdrawal from GABA-B agonists that Vieno has endogenously.

[Mind_Paralysis]

Hmm... I keep thinking back to that part about endocytosis - it would appear as if this gene, GPM6A, controls a lot of very, very important things - but one thing which it does, is to cause cells to WITHDRAW the Mu-opioid-receptors from their surface, and shove them inside instead - causing them to be scrapped and recycled by the cell itself.

 

Could Vieno have some kind of overexpression in his GPM6A? Which then makes his neurons eat up his opiate receptors - causing anhedonia.

 

Check out this further info:

 

http://www.genecards...p.pl?gene=GPM6A

 

Involved in neuronal differentiation, including differentiation and migration of neuronal stem cells. Plays a role in neuronal plasticity and is involved in neurite and filopodia outgrowth, filopodia motility and probably synapse formation. GPM6A-induced filopodia formation involves mitogen-activated protein kinase (MAPK) and Src signaling pathways. May be involved in neuronal NGF-dependent Ca(2+) influx. May be involved in regulation of endocytosis and intracellular trafficking of G-protein-coupled receptors (GPCRs); enhances internalization and recycling of mu-type opioid receptor.

 

 

If that's his issue, it may explain a bit - because something similar is the problem for people with Schizophrenia - overexpression of a gene related to synaptic pruning, which causes loss of white-matter - yet many schizophrenics can have several "clear" windows - times during their life when the disease subsides for a few hours, or days, before it comes back full force.

 

Could this explain why Vieno had moments of refunctioning?

 

I suppose we need to think very carefully about this before we start affecting this gene though... because all of those other functions, are god-daaamn important!

 

 

EDIT:

There are transcription-factors described, MANY apparently, and OVER-EXPRESSION Lysates as well! : D

 

Now we can perhaps figure out if he produces these over-expression lysates?? And maybe we can sort the transcription-factors as well - and one of them is selective for the MOR-recycling-activity??

 

EDIT2:

 

Ok, there are antibodies and everything as well - buut, this is also really, really complicated! I'm utterly lost as to how one uses this data. There are multiple transcription-factors described, but I can for the life of me not figure out what function of the gene these transcription-factors promote! We need to figure out which factor controls Mu-recycling... Anybody know a geneticist? Lol!

 

 

EDIT3:

 

HOLD!

 

There may be a better, more easily deciphered target... Micro-RNA23B!

 

As per this study, which I posted earlier:
 

Post-transcriptional regulation of mouse mu opioid receptor (MOR1) via its 3' untranslated region: a role for microRNA23b.

https://www.ncbi.nlm...act&holding=npg

 

Inhibiting production of this Mir23b may be a much better way to go about it - it's actually involved in several forms of cancer, so shutting down this baby may only be beneficial!

 

We propose a mechanism in which miRNA23b blocks the association of MOR1 mRNA with polysomes, thereby arresting its translation and suppressing the production of MOR1 protein.

 

 

Yes indeed... this may be quite the thing...

 

EDIT4:

 

Err... seems like it suppresses several other forms of cancer - most notably PROSTATE Cancer! God-damnit...!

 

 

EDIT5:

 

Starting to look at it from other points of views - are you guys really certain he doesn't have some form of neurodegenerative disease? Because, as it stands, this study found that Physical Consumatory Anhedonia, is actually unique and specific to depressed Parkinsons-patients...!

 

Hedonic Deficits in Parkinson’s Disease: Is Consummatory Anhedonia Specific?

https://www.ncbi.nlm...les/PMC3948001/
 

 

As hypothesized, several anhedonia scores varied with age and gender in the whole population or in the PD group. On univariate or multivariate analyses, only physical consummatory anhedonias was specific for PD and only SHAPS scores differed between depression subtypes in the whole population or the PD group.

 

 

 

On the other hand, there's this study which seems to indicate that Consummatory Anhedonia is actually a feature of severe Negative symptoms of Schizotypal diseases...

 

Relationship between anticipatory, consummatory anhedonia and disorganization in schizotypy

https://bmcpsychiatr...2888-014-0211-1

 

...while the negative dimension of schizotypy was characterized by anticipatory and consummatory anhedonia.

 

 

Rather interesting... because if the hypothesis of Synaptic Pruning turns out to be true, then SCHIZOPHRENIA is a degenerative disease as well...!

 

So...

 

Have you guys considered that he may have some form of Schizophrenia Simplex? The time-variable mentioned, age 20-25 is one where the disease flares up.

 

Perhaps, if he does have Schizophrenia Simplex, then DIHEXA will help? Dihexa causes immense synaptic growth - which should counteract the root cause of Schizophrenia.

Edited by Stinkorninjor, 17 November 2016 - 05:49 PM.

[Helllllo]

Would love to get in contact with vieno or at least know how he's going?

[Galaxyshock]

Would love to get in contact with vieno or at least know how he's going?

 

I was last time contact with him in January through email. He decided to give up testing substances and doing research for now, since we've exhausted so many options and any potential drugs are difficult to get and expensive research chemicals. Vieno decided to try and experience life as much as possible given the situation, and then will at some point return to trying to treat his condition when hopefully something new would have turned up.

Edited by Galaxyshock, 20 February 2017 - 03:45 PM.