Study, June/18:Peripheral GABA A receptor-mediated signaling facilitates persist

This study likely has bearing on the persistent pain many of us with post benzo damage experience.

 

The findings are counter intutitive: In the peripheral nervous system, GABA, GABA agonists, and GABA receptor activation is excitatory. Conversely, GABA antagonists can reduce inflammatory states and mitigate pain perception.

 

This is a very interesting study for those of us with long lingering persistent pain post benzo cessation. It could be we've been looking at this aspect all wrong.

 

https://pubmed.ncbi.nlm.nih.gov/29634983/

 

Full text here:

 

https://sci-hub.se/10.1016/j.neuropharm.2018.04.009

 

Peripheral GABA A receptor-mediated signaling facilitates persistent inflammatory hypersensitivity

 

Abstract

 

Unlike in the central nervous system (CNS), in the adult peripheral nervous system (PNS), activation of GABAA receptors (GABAAR) is excitatory because of the relatively high concentration of intracellular chloride in these neurons. Indeed, exogenous GABA and muscimol, a GABAAR agonist, exacerbate acute inflammatory hypersensitivity in rodents. However, it remains unclear whether peripheral GABAAR and the endogenous GABA play an important role in persistent inflammatory hypersensitivity. In this study, we thus investigated how peripheral GABAAR affects pain hypersensitivity by using the complete Freund's adjuvant (CFA)-induced persistent inflammatory pain mouse model. We found that intraplantar (i.pl.) administration of GABAAR antagonists, picrotoxin, and 1(S),9®-(-)-bicuculline methiodide significantly inhibited both spontaneous nociceptive (paw licking and flinching) behavior and mechanical hypersensitivity in CFA-injected mice at day 3 (D3), but not in naïve mice. Interestingly, CFA-induced mechanical hypersensitivity was significantly reversed by anti-GABA antibody (anti-GABA, i.pl.). In addition, RT-qPCR revealed that glutamate decarboxylase Gad1 (GAD 67) and Gad2 (GAD 65) mRNA expression was also upregulated in the ipsilateral hind paw of CFA-injected mice at D3. Finally, 5α-pregnan-3α-ol-20-one (3α,5α-THP), a selective positive allosteric modulator of GABAAR, produced mechanical hypersensitivity in naïve mice in a dose-dependent manner. Taken together, our results indicate that peripheral GABAAR and endogenous GABA, possibly produced by the inflamed tissue, potentiate CFA-induced persistent inflammatory hypersensitivity, suggesting that they can be used as a therapeutic target for alleviating inflammatory pain.

 

I don't understand that study.  It's too complicated.  Could you explain it to me.

This study says something that is the opposite of what I've always assumed to be the case.

 

In the brain, GABA and GABA receptors are inhibitory - they slow down the firing of nerves and slow down the entire central nervous system. That's why they calm anxiety.

 

I've always assumed that outside the brain, out in the body, in the peripheral nervous system they did the same thing.

 

This study says the opposite. It says that GABA and GABA agonists are excitatory in the peripheral nervous system - they make nerves fire faster and they sensitize the nerves, specifically those that are involved in sensing pain. It even implies that GABA and GABA agonists are inflammatory.

 

I'd always assumed that the pains in my body were because I wasn't making enough GABA or that GABA receptors in the body had become dysfunctional like we think they may have in the brain. But, the opposite might be true. It could be that once we stopped taking benzos, or z-drugs, that as we got out of the acute stage our body tried to compensate by making more GABA out in the peripheral nervous system, making more peripheral GABA receptors, or both. That would take a little time and it might explain a few things that have been a mystery to me.

 

1.) I did have a lot of muscle spasms in acute withdrawal, but as acute withdrawal carried on and started to pass, the muscle spasms started to get better.

 

2.) At around the 4 month mark, I started to get new pains in my body - in particular the soles of my feet. Eventually I also had pains in the fingers and hands.

 

3.) As time went on, maybe another 6 months, I started getting pain in my ribs and on the sides in the flanks. Or at least that's when those pains got to be really debilitating.

 

4.) It has always been a mystery why there was a lag between when I tapered off, and when these new body pains got so bad. Maybe it took awhile for the body to overcompensate and make too much GABA or make other changes that set off this excitatory activity.

 

5.) GABA supplements don't cross the blood brain barrier. But they should distribute in the body outside the brain just fine. So I reasoned that if GABA supplements didn't help my anxiety, at least they might help the pains in my body. They did not. In fact, they seemed to make the pain worse. I have never understood that.

 

This paper is interesting in that it might explain some of these weird details that have perplexed me.

 

Also, it says that a GABA antagonist can decrease this hypersensitization in the peripheral nervous systems. Now, for those of us with anxiety issues, that might be a really bad idea since it could well make the anxiety worse. But ....... if you could find a GABA antagonist that did not cross the blood brain barrier it might improve your body pains without making the mental issues worse. There might even be a natural compound out there like this.

 

Anyway, this is a lot of speculation on my part. I could be completely wrong. But it's new information that I haven't seen before and it is interesting that it might have some bearing on the body pains that a lot of us experience post acute withdrawal.

 

 

Thanks, Nathan.  When you find a supplement that will help please let me know. 

Nathan Arizona:  Very interesting.  The topic of receptors causes me to wonder if you are familiar with the following book:

 

Naturally Occurring Benzodiazepines, Endozepines, and their Receptors: Implications for Benzodiazepine Therapy and Withdrawal

Edited By Robert B. Raffa, Diana Amantea

Copyright Year 2022

https://www.routledge.com/Naturally-Occurring-Benzodiazepines-Endozepines-and-their-Receptors-Implications/Raffa-Amantea/p/book/9780367409067

There's also a chapter by Dr. Raffa in the book "The Benzodiazepines Crisis" that addresses "Benzodiazepine Receptors in the Periphery". See Chapter 6:

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277 

Interesting, whenever I take anything GABA related I get an increase in pain. Can be almost Acute like. I assumed it was because my receptors were fried

There's also a chapter by Dr. Raffa in the book "The Benzodiazepines Crisis" that addresses "Benzodiazepine Receptors in the Periphery". See Chapter 6:

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

 

thanks Lapis many  other interesting chapters there also....

There's also a chapter by Dr. Raffa in the book "The Benzodiazepines Crisis" that addresses "Benzodiazepine Receptors in the Periphery". See Chapter 6:

 

https://oxfordmedicine.com/view/10.1093/med/9780197517277.001.0001/med-9780197517277

 

thanks Lapis many  other interesting chapters there also....

 

Absolutely!

Nathan Arizona:  Very interesting.  The topic of receptors causes me to wonder if you are familiar with the following book:

 

Naturally Occurring Benzodiazepines, Endozepines, and their Receptors: Implications for Benzodiazepine Therapy and Withdrawal

Edited By Robert B. Raffa, Diana Amantea

Copyright Year 2022

https://www.routledge.com/Naturally-Occurring-Benzodiazepines-Endozepines-and-their-Receptors-Implications/Raffa-Amantea/p/book/9780367409067

 

Very interesting book. I'll have to buy a copy.