Author Topic: GABAA receptors upregulated in FM patients?  (Read 911 times)

[Buddie]

GABAA receptors upregulated in FM patients?
« on: November 18, 2021, 09:47:38 pm »
Happened across this article which puts forth that GABAA receptors are actually UPREGULATED in fibromyalgia patients.  That sounds opposite to what I would have thought, and they postulate that the GABAA receptors may turn excitiatory rather than inhibitory and respond to Glutamate!?

They suggest that the reason for higher GABA receptor density may result from low GABA and hence receptors upregulate to compensate. IDK maybe it's all about the imbalance between Glutamate vs GABA receptors and not necessarily higher or lower receptor #s vs healthy subjects.  Still - sounds unexpected to me.

https://journals.lww.com/pain/fulltext/2020/01000/upregulation_of_cortical_gabaa_receptor.9.aspx

 
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[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #1 on: December 02, 2021, 06:34:55 am »
Interesting though fibromyalgia is caused by Lyme which many people on these boards have even though they are misdiagnosed with Lyme. Untreated Lyme + benzo withdrawal = HELL.
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[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #2 on: December 02, 2021, 02:32:57 pm »
Interesting though fibromyalgia is caused by Lyme which many people on these boards have even though they are misdiagnosed with Lyme. Untreated Lyme + benzo withdrawal = HELL.

Yes, although fibromyalgia has been documented to occur following psychological trauma, and thus is now thought to be neuropathic in origin.  I swear this withdrawal causes FM and Chronic Fatigue, etc, etc...I'm sure the immune system is involved as well, and I actually feel better following my flu and COVID shots.  Go figure.  The whole process is maddening.
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #3 on: December 14, 2021, 01:59:18 am »
Happened across this article which puts forth that GABAA receptors are actually UPREGULATED in fibromyalgia patients.  That sounds opposite to what I would have thought, and they postulate that the GABAA receptors may turn excitiatory rather than inhibitory and respond to Glutamate!?

They suggest that the reason for higher GABA receptor density may result from low GABA and hence receptors upregulate to compensate. IDK maybe it's all about the imbalance between Glutamate vs GABA receptors and not necessarily higher or lower receptor #s vs healthy subjects.  Still - sounds unexpected to me.

https://journals.lww.com/pain/fulltext/2020/01000/upregulation_of_cortical_gabaa_receptor.9.aspx

Our issue isn't that we don't have enough GABAa receptors... The issue is the gabaa receptors we have don't have the right subunits!
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #4 on: December 14, 2021, 04:57:27 pm »
Yes I have read that  theory....Next question:  What can we do about THAT?!
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[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #5 on: December 14, 2021, 05:54:57 pm »
Yes I have read that  theory....Next question:  What can we do about THAT?!

According to this paper (https://pubmed.ncbi.nlm.nih.gov/18180303/), we must activate protein kinase C! (But I don't know how we can do that...)

Here's a quote from the abstract of the paper:
"Here we show that activation of protein kinase C increases alpha1 subunit levels via phosphorylation of CREB (pCREB) that is bound to the GABRA1 promoter (GABRA1p)."
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[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #6 on: December 14, 2021, 10:22:45 pm »
Yes I have read that  theory....Next question:  What can we do about THAT?!

It's not a "theory". It's a scientific fact.

Tolerance to diazepam and changes in GABA(A) receptor subunit expression in rat neocortical areas

C Pesold 1, H J Caruncho, F Impagnatiello, M J Berg, J M Fritschy, A Guidotti, E Costa

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PMID: 9200730 DOI: 10.1016/s0306-4522(96)00609-4

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Abstract

Long-term treatment with diazepam, a full allosteric modulator of the GABA(A) receptor, results in tolerance to its anticonvulsant effects, whereas an equipotent treatment with the partial allosteric modulator imidazenil does not produce tolerance. Use of subunit-specific antibodies linked to gold particles allowed an immunocytochemical estimation of the expression density of the alpha1, alpha2, alpha3, alpha5, gamma(2L&S) and beta(2/3) subunits of the GABA(A) receptor in the frontoparietal motor and frontoparietal somatosensory cortices of rats that received long-term treatment with vehicle, diazepam (three times daily for 14 days, doses increasing from 17.6 to 70.4 micromol/kg), or imidazenil (three times daily for 14 days, doses increasing from 2.5 to 10.0 micromol/kg). In this study, tolerance to diazepam was associated with a selective decrease (37%) in the expression of the alpha1 subunit in layers III-IV of the frontoparietal motor cortex, and a concomitant increase in the expression of the alpha5 (150%), gamma(2L&S) and beta(2/3) subunits (48%); an increase in alpha5 subunits was measured in all cortical layers. In the frontoparietal somatosensory cortex, diazepam-tolerant rats had a 221% increase in the expression of alpha5 subunits in all cortical layers, as well as a 35% increase in the expression of alpha3 subunits restricted to layers V-VI. Western blot analysis substantiated that these diazepam-induced changes reflected the expression of full subunit molecules. Rats that received equipotent treatment with imidazenil did not become tolerant to its anticonvulsant properties, and did not show significant changes in the expression of any of the GABA(A) receptor subunits studied, with the exception of a small decrease in alpha2 subunits in cortical layers V-VI of the frontoparietal somatosensory cortex. The results of this study suggest that tolerance to benzodiazepines may be associated with select changes in subunit abundance, leading to the expression of different GABA(A) receptor subtypes in specific brain areas. These changes might be mediated by a unique homeostatic mechanism regulating the expression of GABA(A) receptor subtypes that maintain specific functional features of GABAergic function in cortical cell layers.

GABA-induced uncoupling of GABA/benzodiazepine site interactions is mediated by increased GABAA receptor internalization and associated with a change in subunit composition

M L Gutiérrez 1, M C Ferreri 1, M C Gravielle 2

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PMID: 24215979 DOI: 10.1016/j.neuroscience.2013.10.077Free article

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Abstract

Persistent activation of GABAA receptors triggers compensatory changes in receptor function that are relevant to physiological, pathological and pharmacological conditions. Chronic treatment of cultured neurons with GABA for 48h has been shown to produce a down-regulation of receptor number and an uncoupling of GABA/benzodiazepine site interactions with a half-time of 24-25h. Down-regulation is the result of a transcriptional repression of GABAA receptor subunit genes and depends on activation of L-type voltage-gated calcium channels. The mechanism of this uncoupling is currently unknown. We have previously demonstrated that a single brief exposure of rat primary neocortical cultures to GABA for 5-10min (t½=3min) initiates a process that results in uncoupling hours later (t½=12h) without a change in receptor number. Uncoupling is contingent upon GABAA receptor activation and independent of voltage-gated calcium influx. This process is accompanied by a selective decrease in subunit mRNA levels. Here, we report that the brief GABA exposure induces a decrease in the percentage of α3-containing receptors, a receptor subtype that exhibits a high degree of coupling between GABA and benzodiazepine binding sites. Initiation of GABA-induced uncoupling is prevented by co-incubation of GABA with high concentrations of sucrose suggesting that it is dependent on a receptor internalization step. Moreover, results from immunocytochemical and biochemical experiments indicate that GABA exposure causes an increase in GABAA receptor endocytosis. Together, these data suggest that the uncoupling mechanism involves an initial increase in receptor internalization followed by activation of a signaling cascade that leads to selective changes in receptor subunit levels. These changes might result in the assembly of receptors with altered subunit compositions that display a lower degree of coupling between GABA and benzodiazepine sites. Uncoupling might represent a homeostatic mechanism that negatively regulates GABAergic transmission under physiological conditions in which synaptic GABAA receptors are transiently activated for several minutes.


Benzodiazepine exposure induces transcriptional down-regulation of GABA A receptor α1 subunit gene via L-type voltage-gated calcium channel activation in rat cerebrocortical neurons

María Florencia Foitzick 1, Nelsy Beatriz Medina 1, Lucía Candela Iglesias García 1, María Clara Gravielle 2

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PMID: 32007495 DOI: 10.1016/j.neulet.2020.134801

Full text linksCite

Abstract

GABAA receptors are targets of different pharmacologically relevant drugs, such as barbiturates, benzodiazepines, and anesthetics. In particular, benzodiazepines are prescribed for the treatment of anxiety, sleep disorders, and seizure disorders. Benzodiazepines potentiate GABA responses by binding to GABAA receptors, which are mainly composed of α (1-3, 5), β2, and γ2 subunits. Prolonged activation of GABAA receptors by endogenous and exogenous modulators induces adaptive changes that lead to tolerance. For example, chronic administration of benzodiazepines produces tolerance to most of their pharmacological actions, limiting their usefulness. The mechanism of benzodiazepine tolerance is still unknown. To investigate the molecular basis of tolerance, we studied the effect of sustained exposure of rat cerebral cortical neurons to diazepam on the GABAA receptor. Flunitrazepam binding experiments showed that diazepam treatment induced uncoupling between GABA and benzodiazepine sites, which was blocked by co-incubation with flumazenil, picrotoxin, or nifedipine. Diazepam also produced selective transcriptional down-regulation of GABAA receptor α1 subunit gene through a mechanism dependent on the activation of L-type voltage-gated calcium channels. These findings suggest benzodiazepine-induced stimulation of calcium influx through L-type voltage-gated calcium channels triggers the activation of a signaling pathway that leads to uncoupling and an alteration of receptor subunit expression. Insights into the mechanism of benzodiazepine tolerance will contribute to the design of new drugs that can maintain their efficacies after long-term treatments.

Thats the million dollar question.. you would have to change gene expression of the gabaA subunits

You would have to find something that increase alpha1, alpha2, alpha3, alpha5, and gamma2 subunits..

« Last Edit: December 14, 2021, 10:39:39 pm by [Buddie] »
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #7 on: December 15, 2021, 09:52:14 pm »
Thanks for this citation.  I hadn't realized there was actual data.  I have long suspected it is a change in gene expression that causes our problems and in order to change it back it takes a long long time (which our experience bears out)....only thing that doesn't make sense is how some very short time users are injured as badly as those who use the drugs long term.  But I guess there could be a subset of individuals who are uniquely susceptible to injury based on their genetics.

And so we have our only answer thus far:  Clean living, good clean whole foods with lots of fruits and veggies, sleep and rest as best we can, limit stress wherever possible and positive attitude with acceptance and gratitude.  Slow progress but at least there is progress.
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #8 on: February 05, 2022, 10:08:14 pm »
Interesting though fibromyalgia is caused by Lyme which many people on these boards have even though they are misdiagnosed with Lyme. Untreated Lyme + benzo withdrawal = HELL.

Yes, although fibromyalgia has been documented to occur following psychological trauma, and thus is now thought to be neuropathic in origin.  I swear this withdrawal causes FM and Chronic Fatigue, etc, etc...I'm sure the immune system is involved as well, and I actually feel better following my flu and COVID shots.  Go figure.  The whole process is maddening.

Fibromyalgia has been shown to be caused by Lyme in scientific studies and so it makes sense that stress would bring it out given the fact that stress lowers the immune system allowing Lyme to take hold in people whose immune systems were previously keeping it at bay. Many people with Lyme either relapse or show symptoms (including "fibromyalgia") during periods of stress. This is very well documented.
Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.

[Buddie]

Re: GABAA receptors upregulated in FM patients?
« Reply #9 on: February 06, 2022, 06:01:01 am »
Happened across this article which puts forth that GABAA receptors are actually UPREGULATED in fibromyalgia patients.  That sounds opposite to what I would have thought, and they postulate that the GABAA receptors may turn excitiatory rather than inhibitory and respond to Glutamate!?

They suggest that the reason for higher GABA receptor density may result from low GABA and hence receptors upregulate to compensate. IDK maybe it's all about the imbalance between Glutamate vs GABA receptors and not necessarily higher or lower receptor #s vs healthy subjects.  Still - sounds unexpected to me.

https://journals.lww.com/pain/fulltext/2020/01000/upregulation_of_cortical_gabaa_receptor.9.aspx

Our issue isn't that we don't have enough GABAa receptors... The issue is the gabaa receptors we have don't have the right subunits!

The issue is we don't know what the issue is. Many of us have speculations. But without research and empirical tests, they are just that. Speculations.

We don't even know if everyone that has long term problems after discontinuing benzos or z-drugs has the same underlying issue. Some people have mainly physical pain. Others have problems with anxiety or depression. Others have cognitive issues. Many have some mix of these. These could have some common underlying pathology, or they could be different root causes. Nobody knows.

One of the most criminal things in this whole fiasco is that the medical profession is assiduously not investigating what these drugs have done and for the most part won't even acknowledge there is a problem.

Suggestions, opinions and/or advice provided by the author of this post should not be regarded as medical advice; nor should it substitute for professional medical care. Consult your doctor before making any changes to your medication. Please read our Community Policy Documents board for further information.