We've learned that NMDA stinks! How's that for aversive learning?

We have enough NMDA to teach us that we don’t want any NMDA. Since NMDA mediates aversive learning, aversive learning may yet eliminate itself. A conundrum of course, but for those with CP, so is life. Here is a quick review, once again, regarding NMDA

It will be recalled that NMDA governs “plasticity” in chronic pain. Plasticity is a term of imprecise definition, but it is used mainly to refer to pathologic upregulation of certain genes with the result of the manufacture of more pain exciters. Because plasticity merely means the manipulation of genetic output we also use “plasticity” to describe any genetically engineered heightened sensitivity at the synapse (gap between neurons).

Typically, we have used “plasticity” to refer to the impact of growth factors, especially NGF, to an extent to create a disease state, either temporary or permanent, wherein genes outproduce their normal complement of pain chemicals.

If central pain were a liver disease, the liver cells would all be morphed into something that is not liver at all, doing who knows what and fouling up the works. In Central Pain, this overproduction is permanent, making the chemical pain pathways so sensitive that they fire with no external stimulus at all. The axons, synapses, and dorsal root ganglia become so hypersensitized they are glad to fire continually, but become utterly overresponsive should any external stimulus actually occur.
The “stupid” firing will be disconnected from discriminative features, and therefore not linked to any beneficial message. This makes the pain not only unbearable but useless, unless you are the ascetic of all times.

There are obviously gradations in between firing too much and firing all the time maximally. CP will take whatever excuse it can get to become worse. Any occasion to fire a pain signal will not be overlooked and if one cannot be found, then one will usually be invented. This inane firing is not one whose source you can easily trace, however, since beyond touch and temperature change, the origins of the central pains are indeterminate. The thalamus is a very sneaky brain part and refuses to monitor itself when it is malfunctioning, so you are left to thread out the DaVinci code of pain with other brain parts which were not designed for the job.

Just to review the drill on why pathological “plasticity” is not regulated or stopped by the normal inhibitory mechanisms of the pain pathways, we must consider how inhibition is eliminated in CP. When there is nerve injury, activation of purine 2X4 (P2X4) receptors in the glia (cells surrounding neurons) causes release of brain derived neurotrophic factor (BDNF). BDNF eliminates the function of GABA (gamma amino butyric acid), which, along with glycine, is the inhibitory chemical of the central nervous system. A moment’s reflection will reveal that removing the inhibitory side of pain balancing is bad.

Similar to any finely integrated control system, neurons are in a constant state of rebalancing and recalibrating. Their inherent design involves something like the act of plank balancing sideways across a log. A person standing on the plank, with feet spread, may shift weight to the right foot a little if the left foot starts to sag. The ordinary brain, mercifully, allows a bit of pain when helpful to prevent further injury, but also recognizes that pain can so distract as to threaten survival.

The brain wants to survive. At the level of the creature, the brain is like a big government agency, whose main function is to perpetuate itself. Pain can go too far to suit the normal brain and cause it to take inhibitory action. Thus, there are these inhibitory functions which damp (as the bioengineers term it) pain by chemical means, ie. GABA. Elimination of GABA by BDNF means that the plank falls to the excitatory side and the nervous system CANNOT right itself to resume a balanced pain system.

There are two steps in the firing process. Nerve in humans are not as fast as the electric circuit in your wall. To increase speed, the ions are making constant rushes toward the membrane and then backing off, making for a fair amount of chaos and noise, but creating some membranes ready to fire much more rapidly than if the ions (charged molecules) were simply standing still. A normal nerve is never at rest. A nerve is like the defensive linebackers who are moving forward in feints toward the line, to be ready to flash across and sack the quarterback. Nerves approach an action potential and then back off. Sometimes they go offside and fire when they shouldn’t, but the brain recognizes the mistake and blanks it out.

In Central Pain you have a defective team and they cross the line of scrimmage as if there were no rules to pain at all. Lacking GABA inhibition, there is nothing a pain nerve loves to do more than to fire. The second step of pain transmission is at the synapse, of which there are typically three between skin and thalamus. A synapse can be like a bottleneck to pain or it can be a slingshot. It all depends on the input between the six thousand or so connections which send axon extensions to the synapse.

Normally half of the connective inputs of synapses are excitatory and half are inhibitory. Positive ions are excitatory and negative ions are inhibitory Because of “anion reversal”, which means eliminatino of the carrier of negatively charged chloride ions in injured neurons, an inhibitory signal at the synapse will be flipped, or reversed to an excitatory signal. The impulse goes over to the dark side and becomes excitatory. Any signal becomes part of the pain process, and life may become almost unbearable. That is why central pain is termed “the most severe pain state known to man”. What worse could you have than pain all the time, no matter what. Admittedly, you could have variations in that pain, just so things don’t get monotonous. Burning dysesthesia and the other Central Pains eddy and fall, just to keep you on your toes. This is all quite exhausting, as pain always is, but variety is the price of life.

The general state of readiness of nerves to fire acts in conjunctions with the workings of nerve transmission at the synapses. The synaptic gaps are control rooms which have input from many sources, once again with provision for both excitation and inhibition. NMDA is a very powerful exciter and most closely linked to chronic pain. NMDA can be viewed as a specific subsystem for slow pain, operating in the context of the general state of readiness of the pain system AT the synapse. Capable of producing plasticity in the gene protein factories, NMDA can get brutal. It is the neverending torment.

Do not be too concerned if “plasticity” can mean several things. The intended meaning usually becomes obvious in the context of what the author is talking about. If all else fails, just think of it as meaning “any process which makes pain worse through chemical means”, the chemicals having their origin in genetic production of pain proteins and other chemicals which by consequence are produced.

All this genetic activity leading to firing tends to make the brain utilize various chemicals at increasing rates, such as sugar or oxygen. These can be tagged with a radioactive tracer and imaged. There is controversy about which areas of the brain “light up” on PET, SPECT, functional MRI, MEG, or tensor MRI. Much of the problem is due to failure to design studies which are dynamic. By inducing or evoking pain DURING the fMRI it becomes easier to see which comes first, the chicken or the egg, the cart or the horse, the pain or the negative emotion.

The close linkage of pain to emotion causes problems in interpretation of images. In no area of brain imaging is this problem greater than in the attendant emotional reactions to pain. Cause can easily be mistaken for effect and vice versa. For example, soldiers faced with death may not feel an initial bullet wound and may fight on, but back at the hospital, the pain system is telling him to lay down and stay down. We can speculate about how emotion is doing this, but for some reason we have a shortage of fMRI studies in soldiers at the actual moment of being shot during war. This leaves the field wide open for unabashed guessing. Add on a PhD, in any field whatsoever, and you have a theory which may be placed in a textbook, or at least a popular book designed for dummies in pain who will grasp at anything for a little relief, (which means any and all of us).

Yes, of course the emotional centers light up during paih, but is it in anticipation of pain, from preexisting emotional distress over ongoing pain, or is it a result of the specific pain being tested for at that moment? The variable of time and chronology of events is not very well controlled in most studies. These areas are very, very shaky in most study designs, with no mention whatsoever in most articles on how the time variable was handled. There will emerge standards to avoid being misled by time, but those standards certainly do NOT exist presently. We do not think placebo is worth anything in CP, and refer to Siddall’s test on it which showed WORSE pain on placebo, but you are free to buy up all the placebo book, or pills, you can get your hands on.

We DO believe in distraction, and in fact, have not found anyone with severe CP who is still alive who has not become expert at distraction. Not all these distractions are praiseworthy, alcohol for example, and most just mean the patient now has two problems, the pain and the addiction. One must choose her distractions carefully, they must be powerful enough to distract, but not so powerful as to destroy. This usually means good books, movies, or music. We could say sleep but we know you aren’t getting much of that because your skin must touch the sheets, and sheets burn the CP subject with dysesthesia.

Back to NMDA. The brain is very much offended by pain, and takes special pains to accomplish aversive learning, so the human can be free from harmful injury. The brain wishes to make use of every pain, to avoid future repetition of whatever caused the pain in the first place. Hence, one would expect the memory apparatus to be linked closely to pain. Our presumptions are borne out. We find that pain and memory are linked not only anatomically, but chemically as well.

What is not clear is whether there is DEDICATED memory assigned exclusively to pain, or whether pain merely hooks into the general memory banks of the brain. Areas of the brain impacting or creating emotional content include such parts as the forebrain, prefrontal cortex, and the limbic system (with amygdala, hippocampus, etc).

Attempts to separate pain into physical pain vs. emotional pain are not favored. A fancy, neuroanatomical way of saying this is that functions of the medial and lateral thalamus are not to be viewed as separate or discrete, just as memory and pain are not truly distinguishable by existing methods.

The cord is like Shrek, er, we mean onions. Onions have layers. In the cord, Layers I and II (REXED layers are numbered on the way IN to the cord) can be more or less thought of as pain layers. Layer II is also called the “substantia gelatinosa” from old time microscope observations and the gross appearance. Layer II is mainly C fibers, with a variant, the marginal fiber, a mystical ninja type of C fiber on the astral plane, occupying Layer I. Marginal cells can supply pain to large parts of the body, up to and including one half of the entire organism. it is a C fiber on steroids.

Sheng Li Xue Bao is a major Chinese medical journal. It publishes articles by Western scientists occasionally, recently one from the Physiology Department in Toronto (Toronto is where pain geniuses tend to hang out, unless they are over in Montreal at McGill) In the 2006 Dec 25;58(6):511-20 issue, Wang GD et al show that NMDA operates to increase synaptic plasticity in Layer V, as well.

These kinds of discoveries are not always welcome since it would be more convenient if one could simply say that pain runs in Layers I and II. However, it is in the nature of science to continually destroy existing knowledge in favor of newer, more accurate knowledge, which will itself be displaced in the ongoing journey of investigation and discovery.

For us, the most interesting part of Wang’s article is his review of NMDA receptors in general. For example, he reminds us that “forebrain NMDA receptors contribute to neuronal spike responses” In academia, forebrain is a kind of buzzword for “emotional”. Even as they agree that it is foolishness to think you can separate physical pain from emotional pain, they turn around and do it by claiming whatever is going on up front in the brain is emotional. (see above on timing issues). This should make you anticpate that frontal cortex NMDA, the big bad chemical of chronic pain, also cranks up the forebrain (emotional) responses to pain.

This seems unfair. If I have pain, I want the emotional response to be damped in CP but injured Nature doesn’t see it my way.

You will recall that the chemical which ups NMDA is glutamate, an excitatory neurotransmitter found largely at the synapse. Glutamate requires calcium to send its signals. Glutamate is the major transmitter for “fast pain” ie. normal pain which speaks up immediately, in the CNS. As Wang informs us “normal synaptic transmission is mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors”. You will find mention of AMPA and kainate throughout this site and should think of them as the chemicals of ordinary pain, which is called “fast pain”.

By comparison, NMDA mediates SLOW pain, or chronic pain, including of course, CENTRAL PAIN. CP subjects may have the WORST of both worlds since there is evidence AMPA and kainate may participate in the evoked (stimulus enhanced) aspect of CP (See “fast pain”, using SEARCH, at this site), while NMDA sustains the spontaneous burning.

Burning dysesthesia is of course spontaneous and omnipresent and needs no stimulus, but it can be evoked temporarily by light touch or temperature change, and when highly evoked, the burning dysesthesia becomes flat out burning torture. (Somehow, even “burning torture” just doesn’t cover it, it is unendurable, unbearable and agonizing).

NMDA receptors geentically enhance (plasticity) NMDA receptor functions, including both PAIN and MEMORY (which is at least aversive learning and probably all learning). NMDA increases sensitivity to tissue injury as well as operating in nerve injury pain. Another important function of NMDA is “long term potentiation” (LTP) of the synapse. LTP is just what you think it is, a prolonged and more potent tendency for pain to be spoken at synaptic junctions by chemical communicators.

Wang et al “present evidence that NMDA receptors not only contribute to normal synaptic responses induced by stimulation of local layer V …white matters, but also contribute to generation of action potentials induced by a depolarizing step applied to the soma (cell body). This means NMDA uses Layer V of the cord to upregulate pain talk at the synapse and also excites the cell body, where the pain proteins are produced which travel out to the nerve endings (which make up any synapse) In other words, NMDA is doubly obnoxious–it has bad breath and also talks a lot, loudly. It makes pain chemicals appear in the cell body and also increases the sensitivity to those chemicalsat the synapse, or nerve junction.

In a recent article we reviewed the very important role of adenylly cyclase. You can review the actions of calcium-calmodulin sensitive adenylyl cyclase 1 and cyclic AMP (cAMP) signal pathways using SEARCH at this site. Suffice it to say that adenylyl cyclase and cAMP likely mediate the effects of NMDA.

Doing a nice job, Wang also pointed out that finding NMDA working in Layer V also explains a possible way the forward cingulum participates in pain. This is not new. The cingulum has been lighintg up on pain fMRI for a long time, but now we know to watch Layer V, once we figure out how to see it discretely on scans. Wang feels this pathway may explain how NMDA really contributes to neuronal plasticity, by recruiting the pain actions of the cingulum. This later statement is speculation, but then again, the Toronto pain scientists are so good, they usually turn out to be right.

We can only express gratitute that the Canadians are looking at pain like real scientists. It is fun to watch them and allows us to maintain hope that the pain sleuths are in the hunt. Hail, Canada, O, Canada! And in this case, we also say “Ni hao”.

Unless the Americans stop reciting urban myths about placebo and get busy studying the chemical cascades of pain, we will be importing knowledge from abroad about pain and quite possibly pain medications as well. This is not bad. Pain relief from whatever source helps all mankind and brings them together.

We need to drag pain out of its evil lair and get a little control. We must stop blaming the victims. We no more deserve central pain than rape victims deserve violation. Central Pain is ruining lives. It is an outrageous relic left over from an ignorant and dark age. For heavens sake, if we can’t make the SCI people walk, let us at least end their pain while we work on the stem cell thing, or else manipulate growth factors so they actually work in regrowing damaged cord. It is past time to let the bright minds attack it. We must root out the killer and destroy it.