[Fentanyl effects on glutamate and GABA release rates from anterior hypothalamus] and [Fentanyl inhibits GABAergic neurotransmission]

[SilentEchoes]

A week ago I had surgery under general anesthesia. I was given propofol and fentanyl. My neuromuscular function has worsened. I've had propofol before without problems. What happened this time? I suspect fentanyl inhibition of GABA progressed my ALS.

The NMDA receptor and the gamma-aminobutyric acid (GABA) receptors are the two main receptors responsible for the actions of general anesthetic agents. Propofol acts primarily on GABA receptors with 10–20% inhibition of NMDA receptors occurring at supraclinical dose. ncbi.nlm.nih.gov/labs/pmc/a...

Fentanyl is 100x stronger than morphine. I get over sedated with morphine, it depresses my breathing. I avoid opiates and instead use delta8 CBD oil for pain management.

I have a genetic defect for pseudocholinesterase (BChE) deficiency. Pseudocholinesterase deficiency occurs in approximately 1 out of every 1,500 to 2,500 people in the United States. BChE is an enzyme in the detox pathway that breaks down acetylcholine and organophosphorus (OP) compounds. Adequate amounts of BChE are required to minimize toxic OP effects.

If I'm given the drug succinylcholine (or another anesthetic derivative of choline) during surgery, the respiratory muscles can become paralyzed and I could stop breathing. The anesthesiologist told me I might have to be intubated after surgery. Thankfully that didn't happen.

In this study, the influence of fentanyl on the release rates of glutamate and GABA is investigated. The results demonstrate that there is an opioid-glutamatergic transmission pathway, located in the hypothalamus and that opioids can activate NMDA receptors. pubmed.ncbi.nlm.nih.gov/300...

In this study, the effect of fentanyl on GABAergic neurotransmission to parasympathetic cardiac vagal neurons was studied. Fentanyl significantly depresses heart rate, the mechanism of inducing bradycardia remains unclear. One possible site of action is the parasympathetic vagal neurons in the nucleus ambiguus (NA), from which originates control of heart rate and cardiac function. These results demonstrate that fentanyl acts on opioid receptors on cardiac vagal neurons and neurons preceding them to reduce GABAergic neurotransmission and increase parasympathetic activity.

researchgate.net/publicatio...

Acute exposure to fentanyl increases susceptibility of pyramidal neurons to presynaptic stimulation. I should not be given fentanyl in the future given my genetic BChE deficiency and anti NMDAR antibodies (autoimmunity).

Humans have a large percentage of the nervous system that is cholinergic including the CNS. Cholinergic nerves also form a major part of the parasympathetic and sympathetic nervous systems.

The wider significance of ACh (acetylcholine neurotransmitter) is in understanding the biological effects of tested toxins and/or medical drugs: as any immunological effects of acetylcholinesterase (AChE/BChE) inhibitors can involve both CNS and PNS.

AChE and BChE can be inhibited by a group of secondary metabolites from plants and fungi. Galantamine and huperzine are examples of plant alkaloids used in pharmacology. Alkaloids α-chaconine, α-solanine, tomatine, berberine, palmatine and jatrorrhizine are other metabolites that inhibit cholinesterases.

Organophosphorus compounds are irreversible inhibitors of both AChE and BChE. They bind to the active site of the cholinesterases and easily cross the blood brain barrier. Nerve agents, e.g., sarin, soman, tabun, and some highly toxic compounds, formerly used as pesticides (paraoxon, parathion, malaoxon, malathion), are examples. High toxicity characterizes organophosphorus inhibitors that are used in chemical warfare or as pesticides.

Drugs that inhibit AChE and BChE are used to treat Alzheimer disease. Are we just trading one problem for another?

ncbi.nlm.nih.gov/labs/pmc/a...

Edit: Memantine is used to treat Alzheimer's, it is not an AChE inhibitor. Memantine addresses dysfunction in glutamatergic transmission, while the AChE inhibitors serve to increase pathologically lowered levels of the neurotransmitter acetylcholine.

I'll expand on neurotoxins and autoimmunity in a separate post.

SE

[Bolt_Upright]

So sorry your neuromuscular function worsened. I am praying it improves.

[glenandgerry]

Very sorry to hear your neuromuscular condition worsened after surgery and sincerely hope the situation improves.My HWP has been on Fentanyl patches for back/sciatic pain for about 4 years (this, after morphine was no longer helping); so I find your very informative post a little worrying (not that I profess to understand all of it). How did you even know you have a genetic BChE deficiency and anti NMDAR antibodies? I'm sure we would never get to find this out over here in the UK with our NHS.

Thank you for posting and bringing all this information to our attention.

[SilentEchoes in reply to glenandgerry]

I'm sharing this information to empower people to take charge of their health. I've begun using direct to consumer testing to supplement my medical care.

G&G, I used Dante Labs in Italy for my genetic sequencing, it was expensive. You can use Ancestry DNA too. I did this with my kiddos and kept their info private. Then you upload your DNA test file into Promethease. promethease.com/

This is another resource

sequencing.com/

With a variety of NDDs running through my family tree - I needed to know. There is hereditary hemochromatosis in my family, I'm a carrier - not affected. Found out my husband is also a carrier through 23me, offspring didn't get the HFE gene from either of us, this was great news. Hemochromatosis is considered a risk factor for dementia, it causes iron overload in the body.

The springboard for all of this was genetic testing for PD at the major university where I live. The genetic counselor recommended Whole Exome Sequencing (WES) but was unable to do it for me. I don't carry the Mendelian genes for Parkinson's. I also don't have the gene mutations linked to ALS.

Dante Labs offers reports that you can buy where specific sets of genes are analyzed. They've been very helpful and answer my questions pretty quickly.

Senquencing.com creates a medical report for drug interactions that you can give to your doctor. My mom, sisters and I are all sensitive to anesthesia and didn't make the connection until much later.

Some things have important consequences and I wanted to be proactive. Quetiapine is contraindicated for me. When my mom was in her last year, Seroquel (quetiapine) was prescribed for hallucinations - she began having TIAs. I wouldn't know to avoid this drug without the sequencing report.

Happy to chat privately if you want to discuss further.

SE

[glenandgerry]

Thanks for this SE.Wow, how fortunate for you that you were able to avail yourself of the genetic testing being offered by the University near where you live.

We submitted Glen's sample for DNA testing to 23andme 5 years ago, then received the report which was interpreted by Integrated Health care, Georgia. No specific genetic abnormalities/deficiencies were flagged but they did recommend several supplements.

I shall look at the 2 links you very kindly gave when I have a little more time. Thank you so much.

[MarionP]

Well evidently you can't have any sort of opiates or medications that block your dopamine receptors Maybe that extends to benzodiazepines for the same general reasons, anything that bumps up your GABA secretion...getting collaborative consults with an anesthesiologist and a cardiologist (seems odd about the cardiologist) and a pain specialist might be of some help there...where I am going there is that for pain and anasthesia there are alternatives that should help.

On chronically managing the iron excess, Have you looked into whether erythrocytapheresis is available as a treatment where you are? A student at Maastricht Univ. may have shown a benefit over standard treatment.

maastrichtuniversity.nl/new...

[SilentEchoes]

Thank you for the info. I think you're right, I need a protocol for anesthesia in my med. record. I try to be proactive with anesthesia after I was given succinylcholine. Suspect I went into cardiac arrest, hospital won't disclose. Whatever happened, it was traumatic. I don't think this last surgery went great, but I woke up and wasn't intubated, so I'll take it as a positive. I don't think I have iron overload, possibly pernicious anemia from autoimmunity. My hemoglobin 3 weeks ago was 16. It feels like I'm in a dog fight to get medical care.

SE