In states of chronic stress why does the bodies receptors not become tolerant to things like norepinephrine, yet when taking medications it does?

[sb4]

I have noticed that when taking clonidine it alleviates a bunch of my symptoms, however after a relatively short period of time it stops working. This is presumably due to the receptors it works on (alpha adrenergic 2 receptors) downregulating in response to overstimulation.

Why doesn't this happen to whatever's causing increased noradrenaline in the first place. Like say my limbic system is constantly stimulating a bunch of neurons in my brain to produce adrenaline, that adrenaline will then enter the synapse and over activate the adrenergic receptors which overtime should downregulate to reach equilibrium, but they don't seem to.

What's the difference between drugs and the bodies on overstimulation of receptors in terms of tolerance?

@Hip

 

[linusbert]

how do you know its not already downregulated? and you just feel the effects of the new delta? until it adapts again>

 

[sb4]

@linusbert TBH I don't know that, for example, my norepinephrine is upregulated but I do know I'm in chronic sympathetic overactivation and parasympathetic under activation.

If you took a normal person and gave them a stimulant to activate the sympathetic nervous system (caffeine?) there body will quickly adapt to bring them back to equilibrium. They'd feel more awake and active after consuming caffeine but tired and lethargic when they don't.

However my system seems to be getting the "caffeine" constantly yet not downregulating.

If I understand, what you are saying is that my body generating stress and adrenaline does cause receptors to downregulate but then my body just produces even more and so on.

If this where the case, since its been going on for 13 years, my adrenaline levels should be extraordinarily high and my receptors vanishingly small. Seems unlikely.

 

[wabi-sabi]

I wish I knew this!

The answer may lie with Hans Selye and his description of the stress response and general adaptation syndrome. The idea is that exposure to a noxious stimuli produces a stress response. There are three parts to the stress response 1) alarm phase 2) resistance 3) exhaustion. Phase 3 happens if the noxious stimuli isn't removed. The exhaustion phase is connected with illness. Maybe you (we) are staying in the resistance phase of response (the amped up adrenaline).

Selye developed this model during the Depression with the oncoming gloom of WWII, which I imagine were quite stressful, and at a time when people in general were worried about the stressors of "modern life". I have to think that influenced him. Of course, the answer is still yoga.

https://www.ncbi.nlm.nih.gov/books/NBK349158/

 

[wabi-sabi]

I'm in chronic sympathetic overactivation and parasympathetic under activation.

In a weird sort of way, this can be the body's attempt to compensate for other things that are going wrong. That might be why it isn't turning off. And of course, there is the emotional stress of having ME/CFS that neve seems to go away no matter how much I try to relax.

For example, my cardiologist doesn't think beta blockers would be a good idea for my OI, even though that's a common medication for POTS. Turned out she was right- my OI is best treated with mast cell stabilizers because it's partly driven by the MCAS. Mast cell stabilizers bring my heartrate down and make me feel a bit better.

Now, I don't know why so many of us have this adrenaline issue (and I still have it even with the mast cell stabilizers), but the body has an awfully complex web of interactions.

 

[Hip]

Why doesn't this happen to whatever's causing increased noradrenaline in the first place. Like say my limbic system is constantly stimulating a bunch of neurons in my brain to produce adrenaline, that adrenaline will then enter the synapse and over activate the adrenergic receptors which overtime should downregulate to reach equilibrium, but they don't seem to.

That's a good question. I don't really know why the sympathetic nervous system (SNS) can remain persistently activated without down-regulating its receptors.


But the SNS works in conjunction with the parasympathetic nervous system (PNS), with the PNS when activated countering the effects of the SNS when activated, and vice versa.

So if the PNS is chronically under-activated, this would lead to an activated SNS having stronger effects than it would normally. So what appears to be SNS overactivation may in part just be PNS under-activation.

There is a concept named sympathovagal imbalance, which is where there is excessive SNS activity relative to PNS activity.



I wonder what would happen if Mestinon were taken in conjunction with clonidine? Mestinon activates the PNS, and some ME/CFS patients find Mestinon generally helpful, and it seems to be a PEM buster for some patients. Though clonidine has a lot of drug interactions, so caution would be necessary.

All types of adrenergic receptor when stimulated activate the SNS, except the alpha-2 adrenergic receptor that clonidine stimulates, which actually act as a brake on the SNS.

So if taking clonidine and Mestinon together, you would be putting the brakes on the SNS from both sides: activating the alpha-2 adrenergic receptor brake within the SNS, and activating the brake from the PNS side as well.

An activated SNS inhibits some aspects of antiviral immunity (the SNS causes T-cell exhaustion), so I've often wondered whether a chronically activated SNS might be the reason ME/CFS patients do not clear their viruses and so remain ill. It could also explain how in rare cases, some ME/CFS patients get better from relaxation psychological techniques, which may be calming the SNS.



I've tried clonidine, but it often (but not always) causes me to get a wave of tiredness around 1 or 2 hours after taking it.



One study found that clonidine also activates the mu opioid receptors, which of course are highly subject to tolerance build up. So maybe this might be the source of the loss of effect you experience with clonidine.

 

[Gijs]

@linusbert TBH I don't know that, for example, my norepinephrine is upregulated but I do know I'm in chronic sympathetic overactivation and parasympathetic under activation.

*

I aks myself this guestion almost 30 years, what causes this overactivation.
My first thought was and still is that the parasympathetic system is broken. For this subgroup of ME patiënts i think stimulation of the PNS could be a treatment. There could be autoimmunity to these recpetors. The antibodies can act as a blocker or stimuli. So, it is also possible that our antobodies are keeping stimulated those adrenal receptors or blocked them.

 

[sb4]

Maybe you (we) are staying in the resistance phase of response (the amped up adrenaline).

This could very well be the case. It certainatly feels like I stuck amped up on adrenaline chronically.

In a weird sort of way, this can be the body's attempt to compensate for other things that are going wrong. That might be why it isn't turning off.

I do think it is compensating for poor blood flow. For example when taking clonidine I would have brief periods where my bounding pulse would settle down, but also my tolerance for walking etc would fall, I would feel more lightheaded. That state is still much preferable to the one I'm currently in.

I have taken L-Theanine the last 2 nights and whilst it resulted in my limbs feeling relaxed and warm (super rare for me) my heart compensated by beating faster (and still bounding just slightly more weakly) and this is whilst lying down trying to sleep in the middle of the night.

What I don't get is if my blood flow is bad then why does lying down bring minimal relief from the bounding pulse? Surely its easier to pump when horizontal. All I can thick is my arteries are stiff with constant sympathetic activation, or for some reason my blood needs pumping extra hard to get to the cells.

So if the PNS is chronically under-activated, this would lead to an activated SNS having stronger effects than it would normally. So what appears to be SNS overactivation may in part just be PNS under-activation.

There is a concept named sympathovagal imbalance, which is where there is excessive SNS activity relative to PNS activity.

I think you might be right. There is probably a window of acceptable levels of adrenaline / acetylcholine. I could be stuck at the high end of adrenaline and the low end of acetylcholine. Still though, if I took something to lower adrenaline slightly you would think it would still be in range enough that no adaption occurs.
Perhaps poor blood flow or something "senses" this lack of adrenaline and sends signals to produce more after a while leading to the medication been overwhelmed by even more adrenaline.

I wonder what would happen if Mestinon were taken in conjunction with clonidine? Mestinon activates the PNS, and some ME/CFS patients find Mestinon generally helpful

I would like to try Mestinon however I have never been prescribed it. Maybe I should order it online. I'll try to bring it up when I have my telephone appointment with the cardiovascular team in London in 2 weeks.

An activated SNS inhibits some aspects of antiviral immunity (the SNS causes T-cell exhaustion), so I've often wondered whether a chronically activated SNS might be the reason ME/CFS patients do not clear their viruses and so remain ill. It could also explain how in rare cases, some ME/CFS patients get better from relaxation psychological techniques, which may be calming the SNS.

This does make a lot of sense. Perhaps this is why I've been ill for 13 years? My Sympathetic Nervous System is been stuck on 24/7 that whole time without a break.
Perhaps I'm stuck in a loop where the virus causes endothelial damage or something that inhibits blood flow and my bodies response to poor blood flow is sympathetic activation which inhibits antiviral activity meaning it is never properly cleared out and the cycle continues.

 

[sb4]

I aks myself this guestion almost 30 years, what causes this overactivation.
My first thought was and still is that the parasympathetic system is broken. For this subgroup of ME patiënts i think stimulation of the PNS could be a treatment. There could be autoimmunity to these recpetors. The antibodies can act as a blocker or stimuli. So, it is also possible that our antobodies are keeping stimulated those adrenal receptors or blocked them.

I did the CellTrends test years ago that test for antibodies against the beta adrenergic and muscarinic receptors and I came up clean, with no antibodies. Not sure how reliable that test is and there could be other receptors involved in the autonomic nervous system that have antibodies causing problems.

Another bizare thing is the kind of paradoxical reaction I have to calming things like deep slow breathing. It kind of makes my stress worse as it feels like my heart has to work extra hard to get oxygen around.

I have tried a bunch a vagal nerve stimulating techniques with minimal success. I am half tempted to try one of those consumer grade external neck vagal nerve stimulators that sort of look like a taser however they are too expensive.

 

[Florida Guy]

As far as stimulating the pns, that has already been done. You do not need expensive equipment, I was able to use a technique I read about using a tens unit to stimulate the pns via the ears. Tens are designed to deliver a controlled pulse of electricity to the muscles to exercise them but it can be turned down to a lower level. I found that it lowered pulse rate and regulated blood pressure. It no doubt was doing other things too

The units cost about $10 to $30 and a set of clips to connect to the ears cost about $8. Or you can go for lab grade stuff and pay a fortune for the same thing. It will allow you to work with the vagus and its completely painless. Here is an article on it https://www.medicalnewstoday.com/articles/325909

 

[sb4]

As far as stimulating the pns, that has already been done. You do not need expensive equipment, I was able to use a technique I read about using a tens unit to stimulate the pns via the ears. Tens are designed to deliver a controlled pulse of electricity to the muscles to exercise them but it can be turned down to a lower level. I found that it lowered pulse rate and regulated blood pressure. It no doubt was doing other things too

The units cost about $10 to $30 and a set of clips to connect to the ears cost about $8. Or you can go for lab grade stuff and pay a fortune for the same thing. It will allow you to work with the vagus and its completely painless. Here is an article on it https://www.medicalnewstoday.com/articles/325909

I had one on my ear just yesterday, though I never really noticed anything from it. Makes me think the neck thing will be a dud too for me.

 

[Hip]

Yoga is thought to boost parasympathetic nervous system activation. I used to do yoga before I developed ME/CFS, but now I find even the most gentle yoga is quite tiring, more tiring than my daily 20 minute walk, so I rarely do yoga now.

If you attempt yoga, note that when done properly, it's not just an exercise, but also a meditation that involves your conscious awareness. So when you first get into a specific yoga pose, and you are stretching various muscles, you find these muscles are initially taught and don't stretch much.

But then while remaining in the post, you focus your full conscious awareness on your body and muscles, and you find that this consciousness itself will start to relax the muscles, and so increase the stretch. This process connects the body and mind, and relaxes tensions in the body and mind.

This study says:

The present study revealed diminished sympathetic activity and improved parasympathetic activity among the regular yoga practicing participants.

 

[wabi-sabi]

There are low tech ways (like breathing techniques) to stimulate the PNS through the vagus nerve and high tech techniques, like all those gadgets. I don't know which of them work, or which ones work better than others, but my inclination is always to start with the ones that are free.

 

[wabi-sabi]

But then while remaining in the post, you focus your full conscious awareness on your body and muscles, and you find that this consciousness itself will start to relax the muscles, and so increase the stretch. This process connects the body and mind, and relaxes tensions in the body and mind.

I used to do this too and I miss it.

It makes me wonder if some of the low tech ways of stimulating the vagus nerve no longer work for us because of our illness and we need a more high tech way.

 

[sb4]

Interesting about the parasympathetic and yoga hip. I'll give it a go.

@wabi-sabi I'm inclined to agree. I have though tried several vagus nerve techniques and they feel like they have a very minor effect. Perhaps overtime the pathways will build the more you do the exercises.

 

[Florida Guy]

I had one on my ear just yesterday

You have to do it just right. Did you feel anything? Did you read the article?

 

[sb4]

You have to do it just right. Did you feel anything? Did you read the article?

I skimmed the article. I used settings that I found on youtube. I tried it like 6 years ago for a month or so but didn't notice anything. May as well try it again though.

How much did you find it lowered your pulse rate?

 

[Florida Guy]

@sb4 It seemed to lower the pulse about 10% and also lowered bp a bit. Those levels have been lower naturally since me/cfs started so I havent really been using it lately. It will affect the action of the vagus and pns but I don't know if that will help you, you may need something else

 

[sb4]

@sb4 It seemed to lower the pulse about 10% and also lowered bp a bit. Those levels have been lower naturally since me/cfs started so I havent really been using it lately. It will affect the action of the vagus and pns but I don't know if that will help you, you may need something else

I tried it again tonight for an hour, 30 minutes in each ear after the whole day being in large amounts of discomfort and not eating due to my stomach being clamped shut and nauseous (due to vasoconstriction and poor blood flow?). Anyway I focused on the light buzzing sensation in my ear which distracted me from the heart palpitations / bounding pulse, by the end of the session I was calmer and my heart symptoms had lessened noticeably to the point where I could eat some chicken breast and later a chocolate bar.

Now this could be just random as my symptoms vary throughout the day but it's promising enough to warrant further investigation.

I'll use it again tomorrow when the palpitations get bad and see if I can get a similar effect. I might also try using the pads, one under the jaw and one on the neck to try and stimulate the bigger thicker part of the vagus nerve.

Maybe it didn't work all those years ago because I was using the wrong settings. Maybe this time was just a fluke. I guess we'll find out tomorrow.

 

[sb4]

I don't know if it was the vagus nerve thing or just random but my symptoms have changed up on me. Now my pulse is racing but not bounding. I had a chocolate bar around dinner time and my pulse was 100+bpm whilst just sitting down for hours afterwards. This is very unpleasant but much preferable to the bounding pulse I always experience.

I think this is more how normal POTS patients are except mine is still elevated (though not by as much) when lying down.

Makes me believe my heart is compensating for poor blood flow with bounding pulse and if that fails (clonidine, alpha GPC, possibly vagal nerve stimulation) it resorts to racing pulse.