The thing has a name. Why can’t it act like just one thing?
Communication is so poor between those who have central pain that many are completely unaware that the condition may manifest as something entirely different in someone else. Consequently, the chat rooms rarely bother to talk about specifics. Posts commonly refer to “the pain” or “neuropain” as if anyone with Central Pain who is reading the bit will immediately know what the author is talking about. This is THE MOST frustrating part of deriving data from the painonline survey. Will all correspondents PLEASE specify which kind of pain they are talking about. We hope to begin linking symptoms up to specific molecular alterations. It will stop the doctors from thinking you have a screw loose if you describe a symptom which he cannot imagine being linked to a pain state because he lacks knowledge of modern brain science. If you will just take the time to be specific, however difficult that may be in a condition which is vague, but terrible, in the perception, we can get the word out.
The mnemonic “M.D. HAS C.P” has been used for general grouping purposes. It comes from an article published by the International Association for the Study of Pain. The letters stand for:
Muscle Pain,
Dysesthesia,
Hyperpathia,
Allodynia,
Shooting Pain,
Circulatory Pain,
Peristaltic Pain.
Each of these symptoms is described in detail in various articles at this site. The classic symptom is the burning dysesthesia, of course, but lancinating pain and allodynia are just as common, although typically not as severe, even if terrible in their own right. Even the muscle pains can be unbearable. Pins and needles is commonly less severe than burning dysesthesia, but potentially crippling in its insistence (”circulatory pain” can drive you insane) Another common symptom is atopoesthesia, which means inability to sense in three dimensional space the precise location of the body surface.
We also have written on loss of “working memory”, first reported by Bogduk’s famous group in New Zealand. Working memory is something which is frequently impaired in CP, but which is actually more related to distractibility than to what psychologists typically mean when they mention “working memory” loss in other disorders, although MANY in the survey report poor learning ability.
We have no term for the strong tendency for stress to increase the level of Central Pain, acknowledged in the NIH information booklet on CP, and would welcome any suggestions for a name so we can discuss stress effect more effectively. We have already suggested this phenomenon is possibly due to CP changes in the hippocampus, but the ability to use this presumption in coining a term is not yet accomplished, and the concept is not yet proven.
Why should we bother to be specific about our pain. Pain is annoying and the less we think about it the better. Why torture ourselves trying to sort it out. That, however, is the very point. Normal pain (nociception) is very precise, with laser accurate boundaries and a clear nature.
Every doctor knows that the patient who is an absolutely worthless medical historian (My indigestion started right after my daughter got married–whenever that was) and the patient who literally exhausts the doctor attempting to extract the slightest detail from them about other aspects of the medical history can become amazingly articulate about pain (”My pain began around 8:30, just below my belly button, less than fifteen minutes after I threw up”). Normal pain is its own education and almost speaks for you. If you can speak the language, you can do a good job telling the doctor about it. Descriptions of pain location, quality, exacerbating events, relieving events etc. are all so easy to extract from a patient that it is the “One True North” of a medical history. EXCEPT in central pain, where it is the most vague of all symptoms because there is no vocabulary.
Patients assume a doctor who has NEVER experienced that awful mix we call “burning dysesthesia” will nevertheless understand when the word “pain” is thrown in. Doesn’t every doctor know the kind of pain that follows spinal cord injury? No, actually. Almost none of them. They are too busy trying to figure out how to restore motor function. This confounds the entire process.
Central Pain is not really pain anyway, it is usually something much worse, because it is many pains, including a number of the worst. Please, try to avoid using the word “pain” when describing CP to us. Use instead one of the words in the mnemonic, or at least give your own version of what is going on. Most of you are really quite good if you buckle down and give it a try. For example, one correspondent described the tingling of pins and needles, aka circulatory pain, as “champagne pain, pain trailing upward like the trail of bubbles in a drink”. This description is obscure on the surface but more than specific enough for someone who understands central pain. Please TRY to put things into words which give us half a chance to report data meaningfully and accurately to the medical profession. In the end, it is YOU who wins, when your doctor does not look at you as if you are crazy. Not a few of your doctors visit this site. Be specific and be comprehensive. We must work together with the clinicians and that means enduring the impression we must be mistaken, or at least a poor historian, possibly even scornfulness before they realize we are telling the truth and that the pain is probably too severe for accurate description.
Perhaps a guideline on how to read technical articles is needed to help you understand why we need specificity EVERY time you speak of your pain. If you are trying to follow the articles on pain chemistry, you should think of whether the topic under discussion is pain excitatory chemicals (glutamate and aspartate and their target chemicals, which will in turn have their receptors) or pain inhibitory chemicals (GABA and glycine and their target chemicals with their receptors). Two prior articles have been published on an additional, newly discovered pain inhibitory pathway which runs off acetyl choline (cholinergic) as well as affecting the N type calcium channels and these pathways are sure to be important as we watch for the results of drugs which affect them, such as ziconotide. Prialt or ziconotide is injected into the spinal fluid and at effective doses seems to have side effects of “severe dizziness, blurred vision, nystagmus and sedation”, so there is more work to do.
You should still think broadly in terms of excitatory (NMDA) or inhibitory (GABA) chemicals. This article deals with excitatory pathways ie. glutamate and its target, NMDA (n-Methyl-D-aspartate) and the receptors which respond to NMDA, of which there are discrete variations on the theme.
The remainder of this article will describe various observations about the NMDA receptor which will illustrate WHY we want specifics in your language. Hopefully, it will also encourage you because it shows that research WILL be productive, if funds are just made available. We are hoping to make some correlation between chemistry and clinical manifestations, ie. your verbal descriptors. This requires some hard thought and a delivery on your part about what you are really experiencing.
Pain is the result of various acidifying pain proteins which result in fatty acids which hypersensitize the pain chemistry pathways. There is redundancy in these pathways, with lots of backup, since pain has a lot to do with survival. Nature never really intended for us to get CP. We slipped through the cracks. We were supposed to die before pain got this bad, but didn’t. Now we have to become canny, the smartest people on earth about how to make it, because no one is there with us. The PhD’s are working hard with their rats, but no one wants to study you, to listen to you, except us.
We very much want your input because we are convinced articulate lab rats (us, with our lousy English, or whatever language) are so much better than rodential ones. A rat’s verbal response is known in the literature as “vocalizing”. You can do better, although the lab rats squealing as their fur is brushed convince the PhD’s without even trying. So far, no one thinks of rats as “drama queens”. The PhD SEES pain and so he BELIEVES pain. It being socially unacceptable to come into the pain clinic weeping all the time, the clinician does not SEE pain, and does not BELIEVE pain. Rats have a sensory tract which responds to touch of their hair, and when it is hypersensitized, the little guys go crazy to a light brushing.
Humans probably have the same tract, but it is smaller and has not been studied. We know twice as many nuclei in the rat brain as we do in the human brain, notwithstanding that the brain of homo sapiens is 600 times larger. The problem is getting volunteers for research. Among the reasons for this difficulty is the fact that PAIN is painful, we like to survive the experiment, plus rats are not susceptible to the accusation of faking it when they do experience it. Since PhD’s who create CP in these little animals have not the slightest doubt of its reality since they can measure the flood of pain chemicals in the rats, they would not think it necessary to create this in a human. Clinicians who are decidedly human oriented don’t happen to read the rat literature. Hence, the information gap. If only the clinicians were equally informed.
Doctors have an ego, without which they would never have tackled the hard grind of medical school. When they see a problem they cannot fix, they must cope with a blow to the self esteem. They have three choices: deny what the patient is saying, form a multidisciplinary clinic so the blame of failure is spread around, or as a last resort enjoin the hard work of solving the problem. Thanks goodness medicine has more than its fair share of solving the problem type people. These latter are the real docs, the former are a collection of inept, nonreaders, who are entrenched in the old time “religion” of outdated medicine. The mere suggestion that they are not omniscient can give rise to severe penalities, not the least of which is to call you a malinger, a faker, a crock. These people probably should never have been admitted to medical school, but admissions committees are not perfect. The medical degree is to heal. If they wished to administer punishment, perhaps they could have entered some other profession, with that aim.
Again, to understand why research WILL work you must begin by thinking differently about what a protein is. It is NOT one single thing, even if it has one single name. It is an assemblage of things which has been placed together in Nature’s wisdom. EACH of the amino acids, of which there will always be more than 200, usually many more, in a protein, is itself a very complicated piece of work, making complex interactions with surrounding enzymes and other proteins. A protein is NOT like Legos, with repeating pieces, most of which are remarkably alike. That concept comes from DNA where only four base pairs code for all genetic messages. A protein is chemistry’s version of diversity. Each group of amino acids comprising a protein, and frequently each terminal end of any given amino acid in the protein has a VERY SPECIFIC role, often in multiple pathways.
Sometimes, if you change the shape of one protein everything else has to change to make room for it. Sometimes, as in mad cow disease, this shape shifting is fatal, the misshapen protein fragment, the prion becomes the weakest link that makes the whole thing malfunction. If you want to figure out just how the bonding angles line up in large proteins to determine shape, get ready for math that even the most powerful computers cannot handle, but which the proteins can go through in the blink of an eye as they shape shift their bonding angles to accomodate the shifting bulges, rotations, and shrinkages. Think of a large can of sardines where on a given signal, the sardine in the upper right corner is to shift places with the sardine in the lower left. This shuffling is NOTHING compared to what a protein does, just to accomodate one rotation at a bond. They seem far more clever than we are, yet they are part of us. This is LIFE we are talking about, and Nature, even at the cellular level, is no pushover intellectually.
NOTHING matches the complexity of a living organism. Absolutely nothing. No matter what you have heard about how easy it was for life to begin by mixing a few amino acids floated in on comets, mixed with a little bit of primordial muck, and zapped by lightning, you may be interested to know that recent experiments show the earlier stuff to have been incredibly naieve. This is not to say evolution is disproven. On the contrary, it makes evolution, if it did occur, so stupendously orchestrated that the mere complexity is estimated to have taken longer by several orders of magnitude than the time since the big bang. This leaves evolutionists in the tough position of explaining why nature ignores the second law of thermodynamics, or entropy, which means matter will naturally seek the lowest energy level, or randomness. They must invent theories of how entropy doesn’t occur in life processes, even as they know this is nonsense.
Having said this, evolution does make sense IF someone or some thing placed elaborate controls on early gene libraries (almost none of which coded, only three percent of our present genome codes for anything), which were so cleverly arranged that they would eventually unfold into humans, perhaps without any further effort. Many scientists see it differently and they are the ones writing the articles on why genes are likely to spontaneously grow more complex, destined in fact to just that, but we suspect that deep in their hearts, they know that it is all quite dubious and that the fundamental question has not been answered. Where did all this complexity come from?
On this one point all biochemists are in agreement. Life is REALLY, REALLY complex. For as long as anyone remembers, whenever we solve one question in science, we instantly create at least fifty more, which we never before knew to ask. There is, it would appear, NO END to knowledge. We are getting smarter. Brain science discoveries are making a few things clearer, and most things more amazing. We have more questions than we ever had. Paradoxically, this is the measure of progress.
If you keep this nautral complexity in mind, the word “protein” will not mislead you into thinking “one protein, one function”. You will understand that PORTIONS of proteins have a life of their own and that as the protein changes shape, or some portion of a protein moves through a new configuration, made possible by alteration in bonding angles of atoms, as unions are formed or broken, that NEW things will happen, MANY new things. If you realize this, you will not become irritated when scientists start to speak of “subunits” or even “pre-subunits” of proteins. You will see proteins as bits of life glued together and will not begrudge each little bit its role.
With this perspective, we present a few interesting facts about subunits of the NMDA RECEPTORS, of which there are a number. To do this, you must be introduced to a new term, the “post synaptic density” or PSD. THIS is the name of an electron dense structure (which means it is easy to see in the electron microscope) on the far side (brain side, if we are talking about pain) of a synapse. Remember, a synapse is a junction between two neurons.
The PSD (post synaptic density) is considered to be an actual structure because it contains both cytoskeletal and scaffold proteins. Marshall Devor has counseled us here to be careful about drawing conclusions when we know so little about so many of these “orphan” proteins. An orphan protein has no family of chemical interactors we can identify, but you can be sure, they are there for a reason. Quite possibly, the reason for some is pain. Phosphopeptides have always been linked to pain and there are at least 38 of them to ponder in the PSD. Two hundred and forty four proteins have thus far been identified in the PSD, (probably more by the time you read this article) but the function of most is unknown or poorly understood. Consequently, they presently are named by numbers, eg PSD-1, PSD-2, etc.
The two proteins currently of interest in pain are PSD-93 and PSD-95. The phosphorylation state of the PSD is known to modulate synaptic “plasticity”, which basically means the propensity to establish more synapses and the acquistion of functions and relationships which require synapses. Phosphorylation simply means the number of high energy phosphate bonds attached to and activating proteins, (which is discussed in two articles elsewhere at this site). PO4, or high energy phosphate, is the body’s battery, and it is donated by a carrier, ATP. Without a battery, the chemical is inert, so phosphorylation is a big deal. Without it, you just can’t start the show. De-phosphorylation is also possible and shuts things down.
NMDA, the main pain chemical, is involved in far more than pain. It is a general excitatory molecule. For example the regulatory light chain in myosin (a part of a muscle fiber which your child in high school biology can tell you about) is actually an NMDA receptor, which will interact with both NDMA receptor 1 (NR1) and NMDA receptor 2 (NR2). Not to let you off easily, NR2 is very big in pain and at least three varieties of it are being studied in relation to pain. NR1 is required for the calcium flow in neurons of the hippocampus which is linked to calmodulin (notice most excitatory modulators have some relationship to how calcium2+ is utilized–in the hippocampus we are talking about memory and emotion when we mention calmodulin). Most scientists think NMDA uses contractile molecules to help move itself around.
Most hippocampal signalling is done with NR2A, combined with NR1, but if too much NR2B is present, long term potentiation, or “tetanic” excitation in the hippocampus can occur. The relative contributions of these various NMDA receptors in CP is unknown. However, blockage of NR2B eliminates hippocampal long term potentiation. We speak of long term potentiation in chronic pain also, but we do not know if the molecular basis is precisely the same as that observed in the hippocampus. Glutamate receptors (see below on GluR) are also found in the hippocampus and do interact with NMDA, of course. This does make us wonder about the loss of working memory in central pain since the hippocampus acts as a kind of rolodex for the brain. If multiple inputs confuse you easily now that you have CP, it may just be your hippocampus struggling to keep the addresses straight. It also makes us wonder about the well known increase in degree of Central Pain when the subject is under stress. The hippocampus is part of the emotional circuit in the brain (see prior article at this site). Since the same chemicals which whip up emotion could well whip up pain, perhaps we need no more research on this.
Margotl has shown that BDNF blockage downregulates NR2A, but NOT NR2B. (see prior articles on BDNF blockage of GABA-A, a major pain inhibitor in the body) Since reduction in one NMDA receptor often leads to overproduction of another, we smell a possible way into the mysteries of the pain chemical cascade. Membrane associated guanylate kinases are known as MAGUK. MAGUKs regulate synaptic NMDA receptor trafficking in the Central Nervous System. PSD-93, one of the MAGUKs, is found in the dorsal horn of the cord where it co-localizes with and interacts with NR2A and NR2B in pain related activity. PSD-93 acts with NMDA receptors to promote neuropathic pain. Tao et al in J. Neuroscience Jul 30 2003 showed that elimination of PSD-93 blocked a model of neuropathic pain in rats. We would certainly like to see more work in this area. More than one scientist has reminded us that the money is just not there at this time.
How do these chemicals know where to go? There is one “molecular moving company” known as the “kinesin superfamily”. The Kinesin superfamily proteins (KIF) move receptors along the microtubules (passageways which form on demand from structural proteins) inside a cell to their destination. We do not know the signalling molecule which begins the movement of NMDA receptors. KIF17 moves the specific NMDA receptor NR2B, but the significance of this in Central Pain has never been studied. Money problems again.
Studies in the retina have shown that Calcium 2+ dependent calcineurin accelerates the decay in NMDA receptor currents, and in this location acts in DIRECT OPPOSITION to protein kinase A, a pain chemical. Calcineurin has already been identified as the de-phosphorylater of NR2A, which is thought to be the mechanism by which activation of receptors in the retina are rapidly shut off, making quick changes in vision possible. Several in the survey have confirmed that in CP if the visual field is briefly interrupted, as when someone walks in front of you when you are looking at the TV, there is an upset or disturbance, where you are a bit visually lost, which is not normal, as you lock back onto the TV picture. We must wonder if adequate levels of NR2A are integrating smoothly as they shoudl or if vision readjustment is slightly compromised. GluREpsilon2 in the forebrain (see below on GluR) increases startle reflexes, whereas GluRdelta2 in the cerebellum has no such effect. The balance of NR2B and NR2A appears to be under careful control, except in injured neurons.
When too much NR2B is produced in the cerebellum, NR2A begins to become ineffective and motor deficits are produced. Incomplete spinal cord patients with central pain do not simply have weakness, they have coordination deficits, indicating a dysfunction in the cerebellum. A strain of mice known as stagger mice have genetic imbalances between NR2A, NR2B, and NR2C. We find this interesting in view of the motor deficits found in Central Pain which are not explainable solely by “spasticity” from spinal cord injury. It is difficult to describe the CP deficits leading to loss of fine motor control well, since respondents usually fail to elaborate on them, but they mimic the uncovering of spinal protective reflexes in that if the person is not paying attention and someone touches them, the limb will withdraw. By contrast, if the person is conscious of an approaching person, they may fail to regulate unparalyzed limbs properly in the more classic form of spasticity. Subtle differences, but nevertheless worth talking about. Long term NR2B overexposure in the cerebellum leads to downregulation of NR2A and motor deficits. The cerebellum controls muscle coordination. Muscle coordination is what fine motor control is all about.
Glutamate stimulates NMDA and itself requires receptors. Glutamate receptors may be ionotropic (voltage) or metabotrophic (chemical) in their activation. The nature of the glutamate receptor is determined by its mixture of components, which have been numbered by the greek alphabet and sometimes numbered secondariy according to which messenger RNA they produce. Thus, we get GluREpsilon 1, and the like. GluREpsilon1 has been shown by Oshima to go directly to NR2A in the swallowing process, and again, we find those in the survey who complain of changes in swallowing. GluREpsilonzeta goes to NR1, while GluREpsilon2 goes to NR2B. We hope to see analyses of both glutamate subunits and NMDA receptor subunits in Central Pain. Congress, if you are listening, send money. (Divert some from the NASA Jet Propulsion Laboratory study on sex in space and send it to the pain unit at NIH. Sex we have no end of, while of pain relief we have hardly made a beginning.)
We have already stated that when one NMDA receptor is underexpressed, the others tend to overexpress. This is undesirable. You can’t make good chocolate chip cookies, if you lack chocolate chips, by adding more sugar. Researchers have produced NR2A knockout mice, which then in turn have neuropathic pain, or at least increased nociception or hypersensitization to Substance P. See Inoue, Brit J Pharm Jan 2000
We have already published two articles here on tyrosine kinase and noted that the presence of tyrosine kinase A (TrkA) is a marker that the neuron containing it is a pain neuron. Fyn is a member of the Src protein tyrosine kinases. Tezuka has shown that Fyn is linked to the phosphorylation of NR2A. Different regions of PSD-95 are linked to Fyn and NR2A. PSD-95 is a molecular scaffold which holds the protein kinases to NR2A. Chazot has shown evidence for an unassociated POOL of size 125 kilodalton NR1 receptors in the forebrain, presumably available to respond to NMDA on a moment’s notice. Activation of these NMDA receptors could perhaps explain some of the metabolic activity shown on fMRI and PET scans in the presence of acute pain.
In developing embryos, the zeta1 subunit of NMDA receptors is found in all layers of the cord EXCEPT layer II, the substantia gelatinosa, which is the pain carrying layer of the cord. The significance of this is not known, but Watanabe feels it explains the functional heterogeneity of NMDA receptors located in various cord layers. Presumably there is a chemical difference, as yet unidentified, in the effects of the same receptor in different locations. Watanabe also showed that zeta1 is found in the trigeminal and dorsal root ganglion but NOT epsilon 1, 2, 3, or 4. (If you see more than one greek letter, you are seeing reference to the messenger RNA associated with a given NMDA receptor, which amounts to the same thing as the receptor).
Thus, we see that it is not sufficient to name a NMDA receptor and stop there. Some of them probably help us and other probably hurt those with CP and need to be blocked. This is surely work that should be funded, but regrettably is not. Until the NIH receives sufficient funding, we must continue to wonder about how the pain cascade of chemicals is operating in the various forms of Central Pain. If you hope for relief, write to your elected officials, urging more money for basic pain research. Also, watch for future articles here on NMDA receptors. They are sure to come. And PlEASE, be specific in completing your surveys. If you have already completed one, but are prepared to be more specific, please do so, indicating that it is your SECOND response to the survey.
