NMDA is the receptor at the far (brain) side of the nerve synapse which is responsible for long lasting pain. Now the NIH scientists are refining just which part of NMDA we have to worry about. So you don’t have to backtrack through the whole site, we also include a little review of pain chemistry so you don’t have to figure out why NMDA is important. (Skip down to the line if you already remember pain chemistry). Many articles here may be more enjoyable if you take a moment to look at the part of the brain under discussion. For a clickable map of the brain, go to http://www.marymt.edu/~psychol/brain.html
We are attempting to update you on what is known about CP. If this article sounds like a hodge podge, we may have done a reasonable job of conveying information, since what is known about central pain IS a hodge podge of information. Do not be discouraged if some of this confuses you. We explain partly to let you know that in CP, it is NOT business as usual in the nervous system. This allows you to challenge your doctor NOT to consider your pain to be “business as usual” pain.
Remember that neuroactive chemicals require a receptor to act, so the receptor is generally of more interest than the neurotransmitter. It has long been suspected that the NMDA receptor had different active sites, since amantadine and memantine, NMDA receptor blockers used in Parkinson’s, were found to be ineffective against SCI central pain, although some scattered reports of benefit from multiple sclerosis central pain have been received.
Ibogaine, which blocks the strychnine-insensitive (glycine) part of the NMDA receptor, has separately been recommended to relieve some of the “agonized” feeling of drug addicts attempting to get clean, but blocking of the glycine aspect has not been reported to stop pain. So the NMDA receptor, like every other huge molecule in the nervous system, is a complicated thing, and we must understand the receptor better to block the pain role of NMDA. We include here a little information on protein folding. Basically it means that the majority of a globular protein is concealed within the structure and not usually available for chemical activity. We requested help from the famous protein folding lab at Stanford years ago, but our colleague there reported that the NMDA receptor is simply too large for their available computing power to determine the structure. Consequently, by simply looking at the chemical composition of the NMDA receptor, without knowing its configuration, we might be going on a wild goose chase to find a blocker which will stop pain, since we do not know which site on the receptor we should be atttempting to block. This entry indicates where some of the research on this is going, toward blocking some of the co workers of NMDA, namely NR1 and NR2.
Nerve transmission is divided into motor nerves (muscle movement) and sensory nerves. Pain travels via sensory nerves. In CP, C fibers, the smallest, slowest, uninsulated neurons sensitize the rest of the nerves, which then crank out the pain. A pain signal generally requires three synapses to get to the brain. Identical or similar mechanisms appear to occur at each synapse, giving many opportunities for control. We speak here as if there were one synapse, bur really there are three.
At each synapse, many connections from interneurons, or neuron “training partners” occur so that the signal going across a synapse is subject to an unbelievable amount of input. Some are saying “fire more rapidly” and others are saying “fire less rapidly”. Most commonly, the brain is inhibiting signal so we can think discrete thoughts. In Central Pain, the brain loses its ability to do this, so we have trouble holding onto a thought, or are distractable, because the pain intervenes, and since the thalamus (brain prioritizer) is messed up, other perceptions and thoughts intervene as well. This is called “loss of working memory”.
We are a bit like the autistic person, who does best if they can be single minded. Distracting inputs immobilize our thinking. Routines bring safety. Avoidance of stress helps us distract ourselves from the frustration of pain. Strong anticonvulsants may quiet the central nervous system, and help a little with the pain.
Like all other problems, pain will fall if we simply do enough to study it. The little spike in activity which occurs in neurons is called the action potential. It sends a kind of binary signal, or one letter morse code to the brain. The frequency of the signal tells the brain that the neurons are sending a pain signal. The action potential is complicated, with positive ions being excitatory and negative ions being inhibitory. The main positive ions are sodium, potassium, and calcium. Each has a number of different channels to handle the current. The channels are manufactured in the nucleus and become embedded in the cell membrane. They open and close at various rates and conditions.
There are extensive articles at this site on all three positive ions which excite the neuron, and on chloride which inhibits it. It is commonly believed that the NaV1.8 channel (a fetal channel which is abnormally expressed by genes in CP) operates on sodium in Central Pain, the CaV 2.2 channel does the same for calcium, pouring out the pain via the TRPV-1 receptor. Substance P, a known pain exciter and neurotransmitter, works on potassium currents by activating the Neurokinin-1 receptor on the far side of the synapse. “Far” means closer to the brain. The signal comes up from the peripherae via the dorsal horn of the cord and goes to the thalamus, then to sensory cortex of the post-central gyrus for location. to the secondary sensory cortex in the parietal lobe for quality, and to the insula for painfulness of pain.
These ions, or charged particles, both positive and negative, operate to establish a gradient or voltage potential, which is stored energy between two “poles” of the membrane, just like a battery. Channels open to cause a firing of the action potential when a generator potential kicks off the process somewhere further down the nerve. Normally, a generator potential can ONLY be initiated at a nerve ending, near the skin or an organ. In central pain, the entire nerve is so sensitized, that a neuron is capable of initiating a generator potential anywhere along its length.
In the disease tetanus, or “lockjaw”, the motor nerve is so sensitized that it gets stuck in “on” and the muscle cannot relax, and ultimately the heart is frozen in contraction, put there by the nerves. In Central Pain, the pain nerves are stuck in “on” and cannot cease sending pain signals. It is a kind of tetanus of the pain apparatus. In most patients, light touch will evoke or exacerbate the burning. The sensitized nerves can generate other central pains such as lancinating pain in muscles, pins and needles, pain in gut or bladder, etc. The greatest pain occurs in the areas which are normally most sensitive, ie. where the greatest number of neurons are anatomically present. This means distally, or away from the CNS. The higher the cord lesion, the greater percentage of body surface which will burn.
The injury need not be complete to initiate the burning of Central Pain, in fact, is NOT complete, by definition. Certain nerves, eg motor nerves, may be complete, while other nerves traveling with blood vessels or otherwise bypassing cord may carry the pain signal. Consequently, severe pain can occur even when there is complete paralysis. One would think such signals would be slight, but when conduction is lost, the brain turns up the gain on the signal, more so when there has been injury. The brain cannot easily do this on the strength of signals it sends out, so motor nerve injury makes for weaker muscle activity, while sensory nerve injury makes for greater nerve activity. This paradox was discovered by Marshall Devor, a friend of this project, and head of the International Association for the Study of Pain. Dr. Devor’s recent discovery of a location which induces general anesthesia in the tegmentum of the mesopontine area of the brain stem, continues to shake up the pain world. A few more like him and pain will not stand a chance. These scientists are knocking at heaven’s door for us.
When the action potential fires, the membrane is momentarily depolarized as currents flow one way. Then, restorative currents reestablish the voltage difference between the outside and the inside and then the cell is polarized again and ready to fire. A neuron can do this as often as fifty times per second. The neurons together makes up a nerve, with larger nerves capable of deriving signal from neuron groups and therefore firing as often as say 1000 times per second. When pain is successfully inhibited, the membrane is hyperpolarized, which means it is much harder for the ion currents to trip a new action potential. Because hyperpolarization tends to prevent firing of an action potential, it is common to read about ion currents that are hyperpolarizing or, when hypersensitized, of depolarizing currents. All this has to do with sodium, potassium, calcium, and chloride, which move to opposite locations to create a kind of battery, ready to discharge or not to discharge.
C fibers are the “army recruiters” of the pain system. In themselves, they mainly just encourage other stronger pain fibers such as the A deltas to join in propagating a pain signal. The front of the spinal cord is organized specially to deal with burning pain, and as the signal ascends, there is a collateral activation of the reticulothalamic tract, as well as the spinothalamic tracts, to make sure we notice the burning, since a burn must normally be dealt with and prioritized. The reticular system is brought in to help us get rid of the burning if possible.
C fibers tend to stay very superficial in the cord, most in the second layer in (Layer II). They are in some way related to the very odd, slow, poorly localized marginal cells in Layer I which seem to be able to sensitize very large portions of the body. Up to an entire side of the body may be sensitized by one tiny marginal cell. They are probably specialized C fibers. The real heavy hauling gets done by the big, powerful, rapid myelinated A fibers, which can send a pain signal as severe as can be felt. C fibers and marginal cells sensitize the A fibers as they come near them in the dorsal horn of the cord. They must recruit the larger fibers to make the pain signal stronger.
Once C fiber sensitization has occurred, then we are really ready to hurt. Think of a sunburn occurring a couple of hours AFTER the exposure to sun. The sensitization by C fibers is now complete, and you won’t be wanting to go back into the sun, or wear a shirt, for some time. In Central Pain, the burn pertains somewhat to temperature change but is more directly related to LIGHT touch. This fact means the “don’t wear a shirt” part of the sensitization is really out of control. Heavy touch hurts a sunburn but only light touch exacerbates dysesthetic burning. It is not known why this is true. The muscles can ache in CP, but pushing into them is described as pleasurable as opposed to painful. This feature is sometimes called “Pleasurable CP”, a term we do not favor.
This spreading of pain notification explains secondary hyperalgesia. If you inject capsaicin in a skin wheal (just under the skin), the zone of skin hypersensitization extends beyond where the capsaicin reaches. What has happened is that the local C fiber has gone to the cord, recruited some A deltas which normally convey pinpoint pain as those A fibers travel through the dorsal cord. These hypersensitized A deltas are acted upon by both synaptic messages and from localized chemical release of pain exciters. Thus, the A deltas do the work of extending the pain hyperalgesia to the secondary area, the area outside where the capsaicin has excited the dedicated C fiber. This means an A fiber sensitized by a C fiber reaching the dorsal horn of the cord, the A fiber being dedicated to one specific area, can nevertheless carry a pain signal which was initiated at an area not supplied by that A fiber.
Movement of the positive and negative ions to the cell membrane is an important part of the action potential process. The ions are carried about by proteins, which can carry them nearer or further apart from the membrane. Also, the pores through which they flow, the ion channels, are made of proteins. As these proteins change their configuration, they become micromachines, moving ions through. This happens VERY rapidly.
Proteins must be activated, or phosphorylated, to perform their tasks. Phosphorylaion is itself done by protein chemistry. ATP generally drops off high energy bonds to other protein. ATP can also serve as a neurotransmitter in its own right. ATP is adenosine with three high energy phosphate bonds attached. A few other energy suppliers exist.
Substances such as NMDA affect other, even more potent pain activators, such as mitogen activated protein kinase, or MAPK, which along with growth factors like BDNF, alter gene expression, which produces amino acids are combined to form peptides which are then combined to form pain exciter proteins. There are many steps at which pain could be interrupted. Opiates work down in the cord, to try to quiet some of the activity there. Current work focuses on the ion channels.
The cited article suggests it would be possible to focus also on the NMDA step. One of the prior articles here suggests that avoiding stress may help at the BDNF step. (BDNF is a growth factor which speeds up gene expression).
A form of the amino acid aspartate contributes to events which lead to rapid depolarization (firing of the action potential). As stated, this article deals with the receptor for the chemical driver of chronic pain, NMDA, which is normally quite inactive, but with changes in calcium metabolism which come from glutamate activity, can awaken and become a sleeping giant of pain, which has just stood up to roar, and keep roaring. The giant is NMDA. It does more than just cause pain, so we must look for the portion that is linked to pain. Painful experience must be remembered by the brain, so many of the pain chemicals also have sites which link to aversive learning, or to memory in general.
Activation of a protein is described by the word “phosphorylation”, the attachment of a high energy phosphate bond, which is like plugging in a battery to your cellphone. “Hello, this is pain calling. The C fiber has instructed that the cellphone will now go into megaphone phase.” It turns out that the pain giant can do nothing without its twin partners, NR1 and NR2, but even more surprisingly, NR2 has an aspect or shape, NR2b, which tries to calm things down when NR1 gets excited. We are learning a lot about what happens in the land of pain giants.
In the nineties, NMDA (n-methyl-D-aspartate) was BIG because scientists had learned that IT mediated chronic pain. AMPA mediates fast pain. NR1 and NR2, when combined with a ligand, more or less constitute the gating mechanism for the NMDA receptor. They appear to be able to adopt more than one configuration, which is probably part of the gating mechanism. There are extensive discussions on NMDA receptors elsewhere at this site.
Glutamate is the main exciter in the cord and aspartate (remember, its evil cousin NMDA is n-methyl-D-aspartate) is the main exciter in the brain, so the synapse, where the action potential upgrade or downgrade site, determines what reaches the cord. At the synaptic junction, glutamate finds NMDA on the far side of the gap, so the synapse nearest the dorsal root ganglion more or less represents the transition between peripheral and central chemistry. NMDA affects plasticity or synapse connectivity, and also mediates excitation. So NMDA can give you pain, and also establish connections (synapses) to make sure you keep on having it. You must try not to become confused over the mainline synapses which carry a signal up to the brain, and the interneuron synapses, which constitute the perhaps six thousand connections between any one mainline neuron and the neurons around it which are modulating the signal going through it according to excitatory or inhibitory input. Gene expression can strengthen or weaken synapses in both the mainline neuron and in the interneurons. Interneurons operate mostly at the synaptic junction. Chemicals which favor pain “strengthen” the synaptic activity which would lead to pain excitation. They do so by production of pain exciters by virtue of altered gene expression to manufacture synaptic pain exciter proteins. The word synapse is loosely used to refer to the actual gap itself and to the area immediately adjacent to the gap. NMDA resides on the far or brain side of the gap.
Both of these amino acids, glutamate and aspartate, are “acidic”. Oddly, some amino “acids” are bases. Amino acids are shaped like a cross with the carbon atom in the center, at the crosspoint. The amino group is to the left and is chemically NH3+. The right arm is COOH, which is usually dissociated into COO-. So there is a proton or H+ to the left to be contributed, and an electron to the right. This configuration makes chains of amino acids, which we call peptides, VERY strong, because of the covalent bond which is produced, with a positive linked firmly to a negative, like the north and south poles of a magnet. Proteins are long chains of peptides.
Certain amino acids like cysteine have sites which can rotate to allow the protein to fold. Once a protein has folded, the H+ ion or the electron- may not be freely available, protected by the surrounding structure. The SH group in an amino acid allows a bend. Proline has a triangle (actually a pentagon which allows a triangular bend) in the left lower corner which also allows a kink, or bend, so that the protein can fold into very complicated shapes, while firmly maintaining all peptide bonds. Because of its odd shape, proline is more properly an “imino” acid. Glutamate has a well exposed, freely available COO- (carboxyl group) which has a tempting electron at the end. Electrons can power things, so it can interact very powerfully with other amino acids such as lysine, which has an NH3 sticking out of a long side chain like a quarterback ready to hand off a ball. Because this article mentions the different configurations of NR1/NR2, which are proteins, we wanted you to understand that certain configurations may change the nature of the chemicals inside the globular protein since the chemicals may not be available when certain shapes are assumed. NR1/NR2 is a kind of micromachine. They are thought to be cyclic or circular.
The nervous system likes glutamate and uses glutamate with its electron as the main neurotransmitter in the nervous system, not only for pain, but for things like memory as well. Aspartate also has this tempting electron sticking out from the COO- end. We have often wondered why working memory is impaired in Central Pain, but the work mentioned below suggests that various proteins around NMDA may actually diminish in pain, affecting the action of glutamate. NMDA is clearly involved in aversive learning, but we do not know its role in ordinary memory.
It is not exactly clear why an acidic amino acid facilitates pain, because membranes do not like to allow an electrically charged molecule (acids are charged with a hydrogen ion) to pass through. Theoretically, it should have been a neutral amino acid which was the guilty party. Yet, we know that acidification of the perineural environment with fatty acids is part of the hypersensitization which marks the central pain process. Nearly everyone with burning dysesthesia remarks that it feels like “acid under the skin”, and we may merely be perceiving the remarkable acidification which has developed around our pain nerves. The burning is agonizing, and most resembles a “chemical burn”.
Of some comfort to the relatively small number of those who suffer from Central Pain is rhe rather large number of pain conditions which are thought to result from Central Sensitization. We have stated elsewhere, that CS is simply anything which cranks up the NMDA for a prolonged period. NMDA is stimulated by glutamate, so the same could probably be said for things which increase glutamate production beyond the level the nervous system can appropriately handle. It is helpful to think of neurotransmitters like plugs we put into a socket. What happens really depends on the appliance hooked to the socket. In the body, we call the socket a receptor. Glutamate is an exciter of the nervous system, but it is the RECEPTOR, the mGluR, which really concerns us. mGlurR means metabotrophic glutamate receptor, or a receptor of glutamate which is produced in response to some metabolic event, such as a pain stimulus or pain chemical. The more mGluR, the more power of glutamate to crank up NMDA, and of course, the greater the pain.
We have praised the work of Michael Iadarola here before, and have contributors here who have worked with him. Iadarola simply never does anything which is not important and so we try to note what he is up to. R.M. Caudle and others with Iadarola have now split the study of NMDA into two protein promoters, NR1 and NR2 and studied what happens with nerve injury. The model is one of peripheral nerve injury (PNI), and we can expect a lot of that since the model is easy to produce and numerically central sensitization (induction of central change from peripheral damage) predominates in the medical pain world. There is no rivalry. What helps PNI will help CP.
What the group found was that phosphorylation or activation of NR1 increased, thereby insuring a greater effect on NMDA. This is perhpas the chemical definition of central sensitization, an increase in NR1. NR2b actually DECREASED in nerve injury, attempting to compensate for the inappropriate levels of excitation by NR1. We now know WHICH protein to attack in the development of pain medicines for nerve injury. We will want something to go specifically against NR1.
Iadarola and those like him are drawing us ever closer to the cure we need, to stop nerve injury pain. How grateful we are for the hard work. We marvel at the success a really bright group of minds can achieve. We hope the drug companies are listening, and making plans which will bring profit to them and relief to us.
Carry on, NIH!!!
See Caudle RM, Perez FM, Del Valle-Pinero AY, Iadarola MJ.
Spinal Cord NR1 Serine Phosphorylation and NR2B Subunit Suppression Following Peripheral Inflammation.
Mol Pain. 2005 Sep 2;1(1):25