• Louise H Connolly MD

Blocking the Signal in Central Sensitivity Pain - The NMDA Receptor



We've talked about this receptor before, but it is such a powerful creator of pain, it deserves a post of it's own. If it is stimulated, you hurt. Glutamate tells the receptor to open up, calcium rushes in, and voila, a whole slew of "excitotoxins" flood the nerve and gives you pain. Now, pain certainly has it's place. We need to pull our finger out of the flame. But here we are talking about inappropriate hyper-intense pain signaling. Too much NMDA receptor activity leads to brain microglial inflammation, then pain out of proportion to what is hurt. Ultimately NMDA over stimulation can lead to severe nervous system malfunction and more. So that's why I decided to show you how this works and what you can do about it.


The NMDA receptor activity is a two edged sword. It actively promotes too much pain, and blunts pain relief. It self perpetuates as well. Pain cannot resolve. Thus it creates a vicious cycle. Too much pain, too little relief, going on too long.


How does our brain work to relieve pain? There are several systems at work. One is the our endorphins, another is our endocannibinoids, another is our resolvins. Endorphins is the "feel good" we get after exercise. Endocannibinoids is the "feel good" we get after a massage. Resolvins actively promote the resolution of inflammation. If all three types can't work then we are in a bind. Exercise and massage don't help. NSAIDS and Opioids just don't spell relief. We've got the block the vicious NMDA cycle first. So here we go!


There are many different parts to the NMDA receptor all influencing the amount of calcium it lets through. First you've got to understand how it works. Then it's best to gently block each component.


To activate the NMDA receptor: a glycine has to land, a glutamate has to land, then the central NMDA pore opens. There is another site on the NMDA receptor (see second diagram) which determines just how open that pore becomes. It's called the allosteric receptor. Then the calcium runs through. Unless you block the open pore directly, like putting a cork in a bottle. A further approach is to calm the presynaptic (pink) neuron from firing too much glutamate. And calm the inflammed microglia down from stimulating glutamate release.


Got it? You need a 1) glycine receptor blocker 2) glutamate receptor blocker 3) allosteric receptor modulator 4) cork in the channel 5) stop glutamate release. 6) decrease microglial cell inflammation I'll highlight which supplements listed below do which. You can pick one of each type. But I'm warning you - you are better off letting me do it. Nutrient, mineral, and neurotransmitter testing can narrow the field. .

Magnesium: (The Cork) We've talked about this mineral before. It directly blocks calcium entry into the cell. Thus if your magnesium is low, it is best to mount a full on frontal attempt to raise it. This process will take a while. It's best to use both a topical (Epsom salt baths, magnesium lotion) as well as an oral magnesium. Type of magnesium? The better absorbed ones are magnesium glycinate, malate, and orontate. Magnesium-L-Threonate may cross more easily into the brain. So I'd probably use this form in combination with one of the others.. It may give more vivid dreams as it prompts night time brain repair.

Lithium: (The Cork) Lithium has a "diagonal relationship" to magnesium. (see above) It's one row down and one space to the right of magnesium in the periodic table. That means it has similar elemental properties and works in similar ways. Lithium at high doses has been used for manic-depressive disorder. Hundreds of milligrams a day can block the toxic "out of control" highs and modulate the lows of bipolar illness. But here we are not talking about hundreds of milligrams, we are only talking at maximum 5 mg a day. Lithium readily crosses into the brain, modulates many different pathways including serotonin, dopamine, GABA and NMDA to bring relief. Indeed, cities where the soil and water supply have naturally high lithium levels have lower rates of both suicides and violent crimes than cities where the lithium water levels are low. Unlike your magnesium levels which change very slowly. lithium orontate, at 5 mg a day, is cheap and can give positive effects in as little as 6 weeks. It does not have appreciable side effects. So both lithium and magnesium belong in your NMDA blocking armamentarium - as much magnesium as you can take without getting diarrhea and just a little lithium.


Zinc: (Inflammation) Magnesium and Lithium block the central channel in NMDA receptor. Zinc has a slightly different effect. Yes, it is an NMDA blocker. But it also is fundamental for proper microglial function. Remember, a lot of brain inflammation is based upon microglial malfunction. The microglia are the brain's immune cells, their white blood cells. And zinc is crucial to white blood cell survival and function. These are the very soldiers of our immune system. Thus we take Zinc if threatened with a cold or the flu. Just to help those white blood cells out. The microglia are the same way.. Too little zinc and they become vulnerable to NMDA over stimulation, malfunction, and viral attack.


OK. We've covered to three main minerals which can directly block the NMDA channel from accepting calcium.. Now we've got to target keeping the two "door locks" closed. The "key" to one of the locks is glycine. The key to the other lock is glutamate, as in monosodium glutamate or MSG. Then the allosteric site. So let's turn to two classes of plant based antioxidants - the terpenes and the flavanoids.


Huperizine A and the Terpenes: (Allosteric/glycine)

Huperizine A is a terpene (sesquaterpine) found in club moss, a primitive type of plant. It acts as an anti-cholinesterase inhibitor, so we'd thought it might work for Alzheimer's disease. And indeed, some studies say it helps a bit. But Huperizine A is also is a NMDA receptor antagonist. It does not directly compete with calcium for entry into the cell. It just keeps the door locked by a totally unique mechanism which is incompletely understood. Thus it's worth adding to your armamentarium. This great gift from great ancient Chinese medicine certainly decreases glutamate induced toxicity.


Apigenin and the Polyphenols: (Glutamate/ Inflammation)

Apigenin is a polyphenol found abundantly in chamomile, parsley and celery. All polyphenols help decrease inflammation but I really like this one for dampening chronic pain. Apigenin features this combination of beneficial effects: It targets white blood cells in the body and microglial cells in the brain, repairing damage to them so they can do their job better. The microglia can then clear up debris, stimulate growth of healthy neurons and relax instead of firing incessantly. Apigenin promotes neurogenesis and is anxiolytic. It allows endorphins to signal properly. It positively modulates glutamate to turn into GABA, a feel good relaxing chemical With limited glutamate, NMDA receptors don't fire as much. Less pain, more pleasure. I like this combination.


Many other polyphenols exhibit NMDA receptor antagonism. Ferulic acid from flax seed, eugenol from rosemary, or lemon balm (the gladdening herb), to name a few. Most work through glutamate modulation. Boswellia Serrata also modulates and decreases glutamate. That's Frankincense, if you've forgotten. Block the glycine receptor? Read on. Both taurine and kyurenic acid do this. Also important is decreasing oxidized homocystiene. It can substitute for glycine to stimulate NMDA.


Taurine: (Glutamate/Glycine/Inflammation)

Taurine is a sulfur based amino acid with a whole host of beneficial actions in our bodies. It lowers blood pressure, helps us sleep, decreases cortisol production and protects us from glutamate induced excitotoxicity. It works on chloride channels, glycine channels, GABA(A), and NMDA receptors. Chloride channels?, GABA(A)? Ok, I'll explain. GABA is the major "calming and soothing" system in your brain. It has a chloride channel in the middle, GABA(A) binding sites, and a benzodiazepine binding site. You got it! That's were your Xanax, Valium, and Ambien affect you. Don't want to be addicted to valium? Try taurine.


More info on taurine: 90% of it is found in white blood cells or microglia so it goes right to the source of neuro-inflammation. In addition, supplementing taurine frees up production of glutathione, the body's master anti-oxidant. What's not to like? Decreasing neuro-inflammation, producing more glutathione anti-oxidant capacity, and hitting GABA - no wonder it makes you feel good!


How do you make it NOT work? Have a lousy diet and bad gut flora. Then you turn taurine into TMAO. (Look this one up if you must. This post is geeky enough already.)


Tryptophan and Kyurenic Acid: (Glycine/Inflammation)

This is the amino acid that makes you sleepy after a turkey dinner. It was a popular sleep supplement in the 1990's but now we use 5- HTP instead. Because some people got excited and wired instead of falling asleep on tryptophan. Here's why. Most people turn tryptophan into 5HTP then into serotonin and finally into melatonin. But in times of inflammatory stress, tryptophan turns into Kyurenic Acid and as such it helps to block NMDA. Kyurenic Acid coats the microglia in the brain in the same way serotonin coats the lymphatic system surrounding the gut. Protection.

You can't supplement Kyurenic Acid directly, but if you have bad habits, taking tryptophan will increase it. For example, you could take up smoking cigarettes. That will crank up NMDA activity. You won't sleep as well, but you will have an increase in Kyurenic acid to help deal with the mess you've created. Unfortunately kyurenic acid can be turned into quinolinic acid which is toxic, raising anxiety, increasing pain. You can block this conversion by exercising.


5-HTP cannot be converted to kyurenic acid. It is dedicated on the path of making serotonin and then melatonin. Thus it became much more popular as a sleep supplement.


Serotonin and Vitamin D:

We all know this one. But serotonin does NOT cross the blood brain barrier. It is involved with GI motility and is stored in platelets not WBC. In the brain, serotonin is directly involved with both sunshine and darkness, Vitamin D and melatonin. Indeed, serotonin cannot even be made from tryptophan without Vitamin D.


The Vitamin D/serotonin link is fascinating. Vitamin D in the brain makes serotonin. Low brain serotonin leads to depression, anger, and aggression. It also leads to migraines, fibromyalgia, and IBS. Vitamin D outside of the brain decreases serotonin. Lower bodily serotonin leads to decreased IBS. Exact opposites!


Melatonin: (Glutamate/Inflammation)

No, it's not just for sleep! And it's much more fundamental and important than serotonin. Melatonin is produced by all living cells, and has been since the first living cells arose from the primordial soup. That cell took UVB radiation from the sun and made Vitamin D. With the new found life, growth and activity also came the darkness, the time of rest, regeneration and repair. Melatonin, Sunshine and Darkness, the rhythm of life, an ancient truth.


Melatonin blocks NMDA excitoxicity, promotes restoration of normalcy, and improves most Central Sensitivity Syndromes. It improves fibromyalgia, IBS and TMJ to name a few. It increases axonal regeneration of nerves and decreases oxidative stress. It detoxifies both the brain and the adrenals. At the cellular level, it potentiates all other antioxidants. It is both fat and water soluble, thus amplifying the effect of both Vitamin C and Vitamin E. And it's effect lasts many times longer than any other antioxidant. Aren't most things better with a good night's sleep? Don't you feel less stress, more focused and in less pain? Fundamental, my dear Watson!


But again, the devil is in the details. Taking a capsule just isn't the same as your brain making more. Just like taking Vitamin D isn't the same as basking in unpolluted sunshine. With melatonin, some people have nightmares and feel hung over with 3 mg. Other researches promote 10 mg to 100 mg every night. For many of people, the more you take, the less it penetrates into the brain.


Indeed, brain melatonin and especially mitochondrial brain melatonin levels are totally independent of oral supplementation. Brain melatonin is 20 times higher than body melatonin levels. Our pineal glands, responsible for most of our endogenous melatonin production, secrete directly into the CNS and defy attempts at tampering. Mitochondrial melatonin production is a whole different story. Mitochondria make their OWN melatonin, and at very high levels. After all, they were originally independent single cells in the primordial soup. All organisms on earth make melatonin, even the first ancient bacteria.


So there is a lot to consider here. I'd certainly try the mighty melatonin. And if I had centrally mediated pain, I'd slowly increase my dose at bedtime as high as I could without side effects. My choice would be a liposomal melatonin spray developed by an ENT. The particle is small enough to slip through the blood brain barrier, penetrate brain cells, and even slip into mitochondria. The melatonin is coated with the same stuff our outer cell membranes are made of. It's the same stuff our mitochondria cell membranes are made of. The coating fuses with cell membranes, and the melatonin is ushered in.


DLPA: (Glycine/Endorphins)

DLPA is a supplement form of phenylalanine, another amino acid. Phenylalanine is the precursor of dopamine, the brain's chemical messenger for reward. It blocks the glycine receptor but does more. DLPA keeps both endorphins and enkephalons around longer in your system. So, if you used to feel really good after exercise, but you can't anymore, DLPA just might be for you. DLPA also is a precursor to Norepinephrine. So if the drugs Savella or Duloxitine have helped you, this may be a more natural alternative.


This post was awfully difficult to write! Yes, it took a whole lot of research. And then it took a whole lot of time to sift it down. At this point, I think I understand it.......maybe. If you are interested, but find this to be too much biochemistry, come in. We'll figure it out. There are many ways to conquer pain.


Next up is the NMDA antagonist drugs. Then off to the endorphins, endocannibinoids, and finally to the resolvins.

LHC MD


#centralsensitivity #NMDA #pain


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