A Primer on What We Think We Know
Let me apologize in advance for the length and complex nature of this page. Even if you have a degree in biochemistry, which most of you don’t of course, it isn’t easy to stay current with the conjecture that’s going on about the cause of Central Pain. This article attempts to pull together some extremely complicated concepts and theories and put them into a form that is at least a little simpler to understand.
While this page is intended primarily for medical professionals, it’s inevitable that patients will study this material in an attempt to understand their condition. Because of that, I hope that the doctors reading this page will have patience as we try to explain some of the fundamentals along the to help the layperson understand these advanced concepts.
No one comprehends Central Pain well enough to fit all the pieces together, not to mention the fact that many pieces are missing and that scientists don’t always agree about the meaning of the pieces we do have. This page attempts to summarize much of what is currently known about Central Pain and the research that shows promise. Since the experts do not agree, we have chosen in some parts to follow our interpretation of the general scheme of things as described by Tony Yaksh, a pharmacologist and researcher at the University of California, San Diego who has done much important work toward discovering the processes behind Central Pain, and in mentoring other researchers.
If you are a Central Pain victim attempting to learn more about your condition, presuming that you succeed in grasping some of this, presenting the information on this page may not make you popular with your pain clinic because you are going to be likely to ask them some hard questions. We will do our best to make you aware of some features (they are too complicated to call them “basics”) of injured nerves that may give you hope that scientists are at least working toward causes and treatments for severe chronic pain.
Many pain clinics find it hard to admit that there is currently no satisfactory treatment for Central Pain. It is worth pointing out that it is almost certainly not possible to tell which type of pain is present by using electrical test devices (which supposedly reach different nerve types with different wave patterns) or by procaine infusions (which supposedly block different nerve types at given concentrations), regardless of how impressive these tests may appear.
Since administration of the “caines” (e.g. procaine and lidocaine) for prolonged times carries high risk of stopping the heart and since the levels of these drugs necessary to block brain sodium channels is probably well above toxic levels in most central pain patients, the attempts to determine central pain with these drugs is scientifically unsound. We are also concerned that this may represent an opportunistic chance for clinics to sell services to third-party payers, such as insurance companies, who seek a way to claim that the patient is well, in spite of their very serious condition. If so, this would be wrong indeed and the courts should reject any claim of evaluation based on lidocaine infusion. Many central pain patients receive no benefit from lidocaine or any other drug.
As Dejerine and Roussy stated nearly 100 years ago, traditional pain relievers are of no benefit in central pain. Also, the symptoms are so complex that a hysteric could never imagine them. For example, hysterics nearly always claim complete numbness in an affected area, while Dejerine and Roussy found that central pain patients report only a partial loss of sensation, along with the burning pain. Furthermore, central pain patients have some form of injury to the central nervous system, which causes them distress in addition to their central pain. Even quadriplegics who are affected by central pain often state that their pain is much more disabling than the paralysis.
We unashamedly include in the following sections some of our own conclusions based on communications from Central Pain patients to PainOnline. Personal accounts from Central Pain patients have value, even if their descriptions may be vague or paradoxical. This ambiguity occurs because the patients are attempting to describe something that is completely foreign and that they can’t adequately explain to anyone who hasn’t experienced these sensations. To complicate matters even further, the lack of discriminative feedback that occurs with some of the symptoms of Central Pain seem designed to confuse, such as the inability to accurately detect where the pain is on the body, or to detect exactly when a stimulus begins. We continue to have faith in the personal accounts of individual patients, just as clinicians of times-gone-by used personal accounts and carefully listened to the patient to determine the nature of a disease. We admit that we will oversimplify many of the concepts described below, but you’ll probably be glad we did, because this is really hard stuff to understand.
First of all, we need to discuss a little neuroanatomy and then some chemistry. It won’t all be clear to you because it either isn’t clear to the experts, and in some cases they simply can’t agree.
In the brain the gray matter is on the outside. This is the cortex and is supposedly where we do our conscious thinking. The inner brain has insulation on its nerve fibers, which causes it to be more whitish in color; hence, the term white matter.
In the cord the gray matter is mostly in the center of the cord, with insulated fibers of white matter tending to occupy the outer part of the cord. Medulla means “middle” in Latin. The spinal medulla is the spinal cord, which sits in the middle of the spinal canal, which is made of bone. Several layers surround the cord. These layers, going in order from inside out are the pia, the arachnoid (where spinal fluid is), and the dura, which is the outermost enclosing layer of the cord. The epidural space is outside the dura.
Pain nerves are a subset of sensory nerves. Pain nerves are named according to their diameter and whether or not they have insulation. A-beta nerves are fatter and insulate. They can respond to lighter stimulus as well as heavy stimulus and are associated with wide dynamic range neurons (WDR neurons), which are nerve cells that can respond to weak or strong stimulus.
Nerve scientists like to divide pain neurons into separate categories. These categories are mechanoreceptors (pressure), thermoreceptors (temperature), and chemoreceptors (chemical). The thinnest nerve cells are C-fibers and have no insulation. They are very slow and require lots of stimulation to fire. A-delta fibers are slightly larger and have some insulation. C-fibers are present in all areas except the dentin of the teeth and are capable of feeling pain that is not particularly well localized, although they can sensitize the A-beta fibers, which are precise in locating the origin of the pain. This phenomenon may explain the 20 – 30 second delay in evocation of touch pain in central pain patients; time for c-fibers to sensitize surrounding nerve fibers.
A cross section of the spinal cord looks like a more or less oval structure. Now imagine an “X” painted across the oval. The arms of the “X” that point toward the back are the sensory nerves entering on either side from the dorsal root ganglion just outside the spine, which is a swollen sort of gathering place for the different types of nerves to join before coming into the cord.
The arms of the “X” that point toward the front are motor and other nerves going out to the body. Signals coming in are called “afferent.” Signals going out from the cord to the body are called “efferent.”
On either side at the back of the cord is an entry point where the nerves of the body go into the cord at each spinal level, from the cervical area (neck) down to the lower levels, including the lumbar nerves. The cord ends at the lumbar levels and the nerves below that, like the sacral, sort of dangle like the tail of a horse (called the “cauda equina”) Each spinal level is numbered, for example, C-1 or L-4 tells you which spinal level is receiving or sending information in that nerve.
Pain scientists are very interested in the organization of afferent nerves entering the cord. The big, fast A-beta fibers go deep into the cord. The layers (or lamina) are numbered beginning at the outside. Their predominance deep in the cord is why A-betas are sometimes called Lamina V cells for quick identification, although they do things in other lamina as well. The thin, slow C-fibers terminate at one of the outermost areas, called the gelatinosa, or Lamina II. In normal people the C-fibers and A-beta fibers don’t talk to each other much, but in nerve injury pain they do little else, probably because the interneurons have been altered in the course of central pain to allow it. Scientists aren’t sure about the intermediate sized A-deltas but they think they possess some of the characteristics of both the thick A-betas and the thin C-fibers.
Pain is considered a crossed pathway, because fibers entering the cord on one side form connections, called synapses, with cells on the other side of the cord before ascending to the lower brain and then the thalamus, where the brain identifies where the sensation came from on the body. Once fibers are inside the cord they have many connections with interneurons, which modify the signal going to the nerve cell as the signal travels up the cord to the brain. The big center in the brain that receives pain input is the thalamus. The thalamus processes pain signals before sending them on to the cortex, or gray matter, which forms the outer portion of the brain.
Pain goes to at least two primary areas of the brain. The main one runs like a stripe across the top of the brain along the ridge (post central gyrus or somatosensory cortex I) and right behind a trough (the central sulcus) that also runs crosswise of the brain about at the top of your head. The main motor cortex also runs along the front of that fold, but sinks deep into the fold.
So the sequence goes something like this. Pain nerve 1 is down in the body. It extends to the cord and passes through a net of modifying interneurons to cross to the opposite side and connect with pain nerve 2, which goes up the cord to the brain stem. Pain nerve 3 leaves the thalamus and goes to the cortex, where the brain processes the sensation you call pain.
Pain also has an emotional component that goes to the submedius and then to the cingulum. This pathway travels in the marginal cells at the outermost layer of the cord, Lamina I. Marginal cells are a few nerve fibers running up the cord, just on the outside of the gelatinosa, the outermost layer of the sensory nerve entering the cord. The experts don’t agree on whether or not the emotional component can really be considered separate from the pain component that goes to the thalamus and somatosensory cortex. Some view and study them separately, and others feel that they are inexorably connected.
Although much of this anatomy is now being challenged and updated as scientists advance their knowledge, it has been fashionable until recently to say that the fibers we have been discussing tell the brain about the presence and quality of pain, but that the emotional aspects of pain travel up the different path to the brain, along the course of marginal cells. The marginal cells are second order neurons to the C-fibers. Second order means they are the second nerve cell (neuron) to carry the pain signal, after they receive the signal from the nerves that send messages to the spinal cord.
The marginal cells don’t seem to care where the pain is coming from, just that it is present and they tell the emotional centers in our brain that they better decide what to do about the pain. Marginal cells are few in number and carry little discriminative information. These cells seem to connect to the anterior cingulum, a part of the brain toward the front. In the days of prefrontal lobotomies, pain patients still had pain after lobotomy but they had less emotion about it. Some think this is because the lobotomy also removed the cingulum.
There is a separate structure at the back of the brain called the cerebellum that lights up like a Christmas tree on a functional MRI when Central Pain is present. This probably indicates muscle alertness for a possible escape from pain. This escape is not going to happen in Central Pain. We don’t know how the cerebellum gets switched on, but it does.
Because it is so much easier to identify and study a peripheral nerve, most early nerve science pertained to peripheral nerves. People with peripheral nerve pain often get help, but Central Pain therapy is very sketchy and largely unsuccessful. Central pain patients have to be careful when going to pain clinics so that they are not dragged through one therapy after another that work for peripheral pain, only to wind up frustrating their doctor who cannot understand why none of the medications help. Central pain is different from peripheral neuropathy. This is not surprising, because many substances that are stimulators in the body are inhibitors in the brain and vice versa.
You have to start with what is known and then learn to ask the right questions about what is not known. Also, you will see that if the scientists can look so closely at peripheral nerves out in the body, they will also look at the brain just as closely when the techniques become available.
Now we get to the really complex stuff, the chemistry of pain. Proteins are composed of amino acids. Peptides are a type of protein that is made of little short chains of amino acids. Peptides are fine tuners, or modifiers, of the pain message.
Chemicals that affect nerve transmission are called neurotransmitters. Where one nerve joins another at the synapse, little packets of chemical form and there are receptor sites or neuron channels where these neurotransmitters bind to cause an effect on the other side of the gap. Released neurotransmitters enter the gap between the nerves and then find receptor sites specific to them on the other side of the gap, in the closest end of the next higher order nerve cell.
Genes in the nerve cell chromosomes produce neurotransmitter proteins. With chronic pain, the expression (protein production) of your genes changes and chemicals are made in the wrong proportions. This causes too much excitation of pain nerves. These excitatory chemicals act on ion channels or receptors in the cell membranes or travel up the neuron and excite the connections (synapses) up the line toward the brain, and also travel down the nerve to excite the nerve endings out on the body surface. Strangely, if the nerve is injured too badly to do this, it can become a “pain cell martyr” as it were, and the neighboring uninjured nerve cells may begin to make these chemicals in sympathy and distribute them up or down the pain pathway. Marshall Devor calls this “crossed afterdischarge.”
Another class of chemicals affecting pain are catecholamines. You probably know one of them already, adrenalin (also called norepinephrine), and you should know it makes the heart beat faster and causes things to get worked up. The sympathetic nervous system is part of the autonomic or unconscious nerves, which supply things like internal organs and blood vessels. The sympathetic catecholamines are divided into Alpha 1 and Alpha 2. Chemicals that stimulate Alpha 2 receptors are said to quiet the sympathetic nervous system when it is part of the pain state. Not all scientists agree on this point.
Clonidine is sometimes injected into spinal fluid, but it is not proven to block sympathetic (autonomic) nerves so as to stop pain, yet there are those who use it and claim benefit. Sympathetic blockade achieved chemically or removal of the sympathetic ganglions surgically have many skeptics, but believers claim early action prevents a worse form of the disease. Skeptics say in many cases the smooth skin, immobile bones, and swelling of nerve injury illness can be explained merely by the disuse of the painful parts, indicating there would be no benefit from sympathetic removal and therefore do not subscribe to removal of the stellate ganglion. Still, it is not unusual for a central pain patient to experience some slight benefit from phentolamine infusion, which suggests some sympathetic component to the pain in some patients. Researchers have used some drugs experimentally to cause sympathetic blockade in lab animals, but these drugs have many undesirable side effects. More needs to be known about this area.
The proteins and peptides we mentioned earlier can chain together to make a shape like a diaphragm, or the Copal shutter in old cameras, which expands to force an opening in the cell wall. Other channels are shaped nothing like a circle and are more like canals or tubules through which ions move. These openings are called ion channels and allow calcium or sodium, among other things, to move in and out of the cell. Each type of channel is very specific and specialized. Ten different sodium channels have already been identified, three or four of them specific to the thin, slow, uninsulated C-fibers. With nerve injury, structures made of excitatory chemicals move from inside the cell to the cell wall itself where they embed, forming a new kind of channel. The abnormal increase in these chemicals moving through the channels at the cell wall adversely affects pain at the synapses between nerves.
Aspartate is an amino acid. When we find it in receptor sites on the receiving end of a synapse it has been modified and deposited as N-methyl-D-aspartate (NMDA). NMDA is very quiet unless the pain signal is massive. It then becomes activated and makes matters much, much worse. Glutamate and glycine are excitatory amino acids.
Gamma amino butyric acid (GABA) is an inhibitory neurotransmitter substance. GABA inhibits pain signals. Glutamate and glycine excite pain signals. Clue; there is not enough GABA present when nerve injury pain is occurring, and at the same time there is too much glutamate.
The Body’s All-Purpose Battery
Now the next part is a little bit easier. A battery stores energy chemically. The energy comes from the voltage difference at the positive and negative ends of the battery. If something connects the two ends, the current flow will try to equalize the voltage and that flowing current supplies electrical energy. Once the energy is released, the battery has to be replaced.
The body uses high-energy phosphate bonds for energy storage. In the body’s “all purpose” battery arrangement, phosphates attach to adenosine. The bonds can be removed and the energy passed to another chemical by attaching a phosphate to (phosphorylating) the new substance, which is done by kinase enzymes. For example, if substance “X” has a phosphate attached, it is called phospho “X” or “p-X,” meaning it is phosphorylated and ready to rumble. To the energy supplier adenosine are attached, one, two, or even three high-energy phosphate batteries. This means there can be adenosine monophosphate, diphosphate or triphosphate (AMP, ADP, ATP).
Many chemical reactions can happen only if phosphate bonds supply energy. The result is that wherever phosphorylation is taking place in the body, more energy is going to be available to make chemical reactions happen. Remember that word, “phosphorylation”, but you can just think “battery power” if you want to. If you were fighting Central Pain you would not want phosphorylation to occur, because it would be excitatory and you want to quiet things in the pain system, so excess phosphorylation in pathways that excite pain nerves is bad. You’ll remember that glutamate excites pain signals and GABA inhibits or quiets pain signals. Many chemicals in nerve cells are inert and do not function unless a phosphate attaches to them. For example, glucose (sugar) is relatively inert, but if something attaches a phosphate bond to it, it becomes glucose 6 phosphate, which is very reactive.
The substances that attach phosphate energy packets to cells are enzymes called kinases. There are kinases for all types of substances including kinases that attach energy booster phosphate to amino acids, such as tyrosine kinase. Putting a phosphate bond on something is like taking yeast out of the refrigerator; things begin to happen. Currently, pain researchers believe that mitogen-activated protein kinase is at the center of the cascade of events causing nerve injury pain. Putting phosphate bonds on membrane receptors and channels makes the transmission of pain signals to higher order neurons much more efficient. Of course, kinases can only act on substances that have already been produced by the genes. Increased pain could come from either faster, stronger kinases, or it could result from something that causes the genes to increase their production of substances for the kinases to act on.
Gene expression means protein production. Genes write for messenger RNA (mRNA) through a process called transcription. When that process actually turns out a protein it is referred to as translation. You might remember from high school biology that the sequence goes DNA > RNA > protein. RNA polymerase the genes are transcribed into mRNA, then mRNA gets the message to transfer RNA, which connects with ribosomes that translate the message into a protein. The production of proteins by genes is called translation.
Many kinases only act on what has already been produced by genes, so they are considered post-translational factors. Mitogen-activated protein kinase (MAPK), however, also probably influences the process of transcription which is the genes writing the information to form mRNA, and so MAPK is considered to have a pretranscriptional effect, too. Also, MAPK can increase the writing of the genetic code to form excitatory substances. In other words, MAPK makes the genes write for more mRNA to make excitatory proteins and then increases the sensitivity of receptors and channels to those very proteins, like some kind of master switch, as Dr. Ru-Rong Ji has stated it. Clue: MAPK is bad if you have Central Pain because it really cranks out excitatory chemicals. It puts the screws to the pain nerves. Medicines controlling MAPK could be a whole new class of pain drug.
We mentioned before that big fast, low threshold, A-beta pain fibers plunge deep into cord reaching to lamina V and the thin, slow, high threshold C-fibers stay out in the gelatinosa, a clear layer at the surface, called lamina I. You recall though that there is a net of nerve cells connected to the second order neurons that have connections to entering A-beta and C-fibers. We called this net bundleinterneurons; among them are wide dynamic range (WDR) neurons that ascend up the cord. Because they connect to both low threshold A-beta and high threshold C-fibers (this connection is called convergence), many interneurons in the dorsal horn can respond at low and high thresholds (weak or strong stimulus), hence they are called WDR neurons. They are second order neurons since they are second in the pain pathway.
The A-beta nerve cells project from a very small area of skin and are quite accurate in identifying the location of a stimulus. A-beta fibers, which contribute to WDR pain, carry very precise information on the space, place, mode and intensity of the stimulus to the lower lateral area of the thalamus. The thalamus and brain can map these signals on the human body surface so you know right where the signal is coming from. We have lots of A-beta nerves.
The outermost layer of the cord is lamina I. This is where we find the marginal cells, which are second order neurons. They receive input from C-fibers and only fire with high intensity pain. The marginal cells are relatively few in number and each cell receives input from a very large area of skin. They don’t seem to be concerned much with the location of the pain. One cell firing generates only general information and only tells you that there is a high intensity pain from somewhere, such as the leg. The marginal cells ascend to the submedius instead of the thalamus, and from the submedius to the cingulum. There is no mapping of these signals according to the part of the body in trouble, but they do transmit some information about the quality of intense pain.
If you touch something hot and drop it quickly enough, you stop hurting. If you contact it long enough, you get a burn. Once you have a burn, if you touch the area, even with something that isn’t hot, the skin will feel a burn. This is called primary hyperalgesia, which means heightened pain. It is referred to as primary because it is in the area of original injury.
Hyperalgesia and allodynia are kind of tied together. Any pain caused by a normally nonpainful stimulus is called allodynia. If skin is hyperalgesic, you may get allodynia. Hyperalgesia refers to pain in a normal nerve. If the nerve is injured then this is calledhyperpathia and it acts in a particular way. Heightened sensation outside the area of injury is called secondary hyperalgesia. Any pain from a normally nonpainful stimulus is allodynia. Pain in an area other than the area touched is called allachesthesia. Hyperpathia, allodynia, and dysesthesia are all part of the pain abnormalities experienced in central pain.
If you isolate a C-fiber nerve and pinch it, you cause a firing that is received by the spinal cord neurons. If you pinch it hard enough, the firing continues for 30 minutes or more. At first, it was thought that this was because the C-fiber had been injured and this was responsible for the continued firing. The pH of the area around the injury drops to the acid range and may go as low as 6 or even 5 in some circumstances (7.4 is normal). These chemicals together have a synergistic effect on firing of the C-fibers. Together they are more potent than any single one alone. What is very interesting is that a C-fiber has specific receptors to bind these chemicals. For example, the prostanoids (of which the prostaglandins are best known) have specific receptors called EP and IP receptors. The injury pattern and chain of receptors devoted to the exciter chemicals is organized and is often very specific.
These same compounds normally have no effect on the big A-beta fibers. The smaller A-deltas may respond if they are of the type called “chemically sensitive,” but we think the A-betas are indifferent to chemically induced pain. Strong pain means pain where the pain fibers fire at high frequency. What if you graph the firing intensity (frequency of firing) of C-fibers in relation to the intensity of an applied stimulus (how hard you are pinching)? If tissue injury chemicals are present, not only can they cause spontaneous firing, they also increase the slope of pain response so that each increment in stimulus causes an even greater increment in the frequency at which the C-fibers fire. This means the pain ramps up quickly on an ever-steeper curve.Intensity of pain is ultimately defined by the frequency at which the nerves fire, not the strength with which they fire.
Now let’s return to the WDR neuron. This is the second order neuron in the cord that connects with both low threshold fibers and high threshold fibers. If we stimulate every second or two, we get a certain firing rate in the WDR neuron. If we continue the stimulation long enough and then shut it off, the WDR neuron will still continue to fire because of the sensitization of C-fibers by tissue injury chemicals described above. The repetitive firing by WDR neurons due to C-fibers sensitization is calledwindup. Overstimulation of A-betas alone does not give windup. Windup is very important. Try to remember it.
Now these A-betas that connect to WDR neurons are usually very precise about informing the brain about exactly where the painful stimulus was applied, but they have connections, or collateral synapses, with other A-betas connected to WDR neurons. Normally, stimulation in a small area of skin only reaches the one WDR neuron that supplies it. However, if A-beta cross-talk occurs, the patient will feel pain in a wide area because the high frequency firing sends out signals to other A-betas, which would normally not fire. The ability to localize pain decreases but the intensity and durability of the pain signal increases.
At this point, even a modest stimulation in the area of skin supplied by these neighboring neurons will give a strong pain response. Note that this supersensitization in WDR neurons, which results in allodynia is now being driven by A-betas, the big boys who are bad news to the brain when it comes to pain. Some A-delta, smaller slow conducting fibers, may be able to drive windup if the stimulus is of the type the fiber was specifically designed for, such as thermoreceptors, but this has not been proven. For now we will say windup comes from A-betas that have been sensitized by C-fibers.
The Significance of Delay
What does all of this mean in human beings? Here is where PainOnline research will be put to use. We have found that those with peripheral pain display the evoked or augmented pain from touch immediately, while those with Central Pain have adelay, usually a matter of 20 – 30 seconds before the pain evokes above its spontaneous, normal, level. This is an important diagnostic distinction that allows clinical differentiation between peripheral and central nerve injury pain. S. Weir Mitchell used the same test to differentiate the site of injury in nerve pain as early as 1872.
We have called this delay in evocation temporal summation or slow summation, a kind of central version of peripheral windup. Doctors who are not experienced with Central Pain may think the delay means the patient is faking, since they are used to seeing the immediate pain in peripheral neuropathy. Actually, the delay for evocation is proof that the patient has Central Pain. We theorize, somewhat paradoxically, that the brain does not like input from high in the nervous system to generate pain, or rather it is not geared to efficient and timely response, whereas the brain is used to pain from the peripherae generating pain and accepts it instantly. Certain endorphin-like structures, such as dynorphin suppress pain and are expressed when neuron genes like c-fos are stimulated into greater transcription by noxious stimulation of the nerve. Dynorphin or other induced chemicals may slow the buildup of evoked pain in the central nervous system, but this is speculation. In addition, the pain relays in the brain are much more complicated than in the cord and inhibitory chemicals may act as exciters if they inhibit an inhibitory pathway (disinhibition).Alternatively, an exciter chemical may excite an inhibitory pathway in the brain, giving a reverse effect from what might be expected from experience with the same chemical when it is in the cord.
Open brain surgery, where the brain itself is cut, is not painful. The cord also cannot generate ordinarily pain. These things do not hold true in Central Pain, where the central nervous system can generate pain. We theorize then that the brain has a bit of time lag before it will accept pain generated in the central nervous system. If touch or temperature change burns you instantly, you probably have experienced an injury to a peripheral nerve. If it takes 20 – 30 seconds for you to notice increased pain from light, persistent touch, you probably have Central Pain, provided that this endures over weeks or months and is not just a sunburn or something similar.
Most Central Pain patients have spontaneous burning pain which can be evoked (greatly increased) by touch or thermal stimulus that would not ordinarily be painful (allodynic hyperpathia). Evoked pain in Central Pain still requires stimulation at some peripheral place in the body, so “windup” is part of it, but there is some time delay, or a slow temporal summation, in Central Pain. It is possible that such pain requires activity in both peripheral C-fibers input and some abnormal behavior in the axons of central nervous system cells.
Perhaps the peripherally initiated windup from touch has to jump some gap or surmount some hurdle before what is going on in the central nervous system can be additive, resulting in evoked pain with slow summation. Ron Tasker discovered that radiostimulation of the spinothalamic tracts (pain tracts in the spinal cord) in normal people yields no response. In those with Central Pain, however, it recreates their burning dysesthesia. Lenz has recorded “bursting” discharges in the thalamus of Central Pain patients that are not present in normal individuals.
Researchers try to simulate nerve injury pain by injecting capsaicin under the skin. Capsaicin is the burning agent of red chili peppers. Those with Central Pain know this does not really recreate our burning dysesthesia, which is a very complex, multifaceted pain; whereas, the pain from capsaicin is a very specific pain as to quality, although similar to central pain burning, it doesn’t localize all that well. Capsaicin induced allodynia is nearly a pure hot sensation, while Central Pain displays complex phenomena and many types of pain.
What troubles researchers is that A-betas are thought to not be chemically sensitive, yet they appear at first glance to drive pain around the capsaicin area. So the capsaicin must be stimulating C-fibers that return to the cord in order to have this expanded zone, (i.e. beyond the area of actual capsaicin injection) which is hyperalgesic for a half hour or so after injection. Dr. Yaksh has commented on this curious situation where you can generate a wide area of secondary tactile allodynia, even though you have stimulated only a few C-fibers in a small area.
In the projected ends of C-fibers in the cord there are small vesicles or collections of excitatory amino acids, such as glutamate and excitatory peptides such as Substance P and CGRP. You remember that channels are small protein structures capable of opening when the proteins that form them contract. We will refer to these channels as one entity, but remember that each type is very specific and specialized. When glutamate is present the calcium channel opens, flooding the area with calcium, which causes release of the neurotransmitters in the little vesicles. Increases in calcium also activate the nitric oxide/cGMP/PKG pathway. Blockade of this pathway stops the pain of injected capsaicin injection. Some researchers refer to this type of pain as calmodulin-related pain. There is felt to be some element of it in ordinary nerve pain. Type II calcium/camodulin-dependent protein kinases have been shown to alter glutamate receptors in parts of the brain. Calbindin abnormalities have also been linked to cognitive changes, which may account for the fact that so many central pain patients report memory and learning changes.
One has to wonder what thalamic impairment can affect. Fear, another common feature of central pain, does not seem remarkable in view of the fact that C-fos expression, long known to be increased in nerve injury pain, is now considered a contributor to fear arising in the cortex. Serotonin, mediator of its own pain modulating pathway, is now known to act through 5-hydroxytryptamine (5HT) to block GABA(A) pathways through activation of protein kinase C (PKC) anchored in the prefrontal cortex, an ultimate destination of come C-fiber activity. (Remember that rats lacking in PKC cannot get central pain.)
Quick vs. Long-lasting Pain
When Substance P is released into the gap between neuron endings it acts on the other side of the gap, on the next higher order of neuron, at what are called non-NMDA receptors. The glutamate causes a quick firing by acting on AMPA and kainate receptors (AMPA/kainite receptors in the second order neuron). Substance P is able to cause a much longer lasting firing by acting on neurokinin (NK1) receptors. So, glutamate = quick pain and Substance P = long lasting pain.
NMDA is also buried in the nerve cell on the other side of the gap, but normally it is unable to fire. It remains quiet. Some researchers believe this arrest is caused by magnesium in the receptor. Newer research by Woolf and others suggests a different mechanism, but the effect is the same. When sufficient sensitization has taken place from release of excitatory chemicals, the magnesium is supposedly washed out and then the NMDA, which is capable of truly large pain signals, can be acted on by glutamate. Note that considerable sensitization must have occurred to kick the NMDA receptors into action, but they can really get the job done when stirred from their deep sleep by Substance P, together with the actions of glutamate. Clue: NMDA is not your friend if you have Central Pain.
Remembering back to our battery discussion about phosphate bonds, cyclic adenosine monophosphate (cAMP) enables protein kinase A (PKA) to allow prostaglandins (inflammatory chemicals) to sensitize nerve endings. However, in rats who inherit a defect in the type I regulatory subunit of PKA, that is, they have defective PKA, they are defective in developing nerve injury pain. Clue: If we could block PKA, it would decrease the inflammation of nerves, and the result would be a reduction in nerve injury pain.
Nerve growth factor prompts nerve chromosomes into action. ERKs are substances by which nerve growth factor (NGF) exerts its action, and we mention them here because ERKs stimulate MAPK (mitogen-activated protein kinase). ERKs are activity dependent, meaning their activation will not happen unless activity is going on in the nerve. It is activated by NMDA receptor stimulation and you’ll recall that NMDA doesn’t start to operate unless really severe pain is going on.
It has been found that ERKs are needed for long-term potentiation of nerve firing. ERKs operate in normal pain nerves and in diseased pain nerves. Clue: you don’t want ERKs activation if you have Central Pain, because it is going to stimulate MAPK, which as mentioned above, really begins to crank out excitatory proteins. MAPK is like a master switch. Of course, you don’t really care about unenergized ERKs because, like many other substances, it isn’t going to do much until a high energy phosphate bond (battery) is attached. It is actually phospho-ERK (pERK) that is the bad guy.
pERK is activated by any C-fiber stimulation, only slightly by A-delta stimulation, and not at all by A-beta stimulation. If it helps, you can think of tiny C-fibers as a baby bear neuron, middle-sized A-Deltas as momma bear, and the big A-Betas as papa bear neurons. pERK only eats baby bears’ porridge, with maybe a tiny taste from mama bear’s bowl.
Nerve growth factor (NFG) is thought to be critical in gene activation in the dorsal root ganglion (DRG) and increases expression of Substance P, CGRF, and BDNF. Activated p38 MAPK phosphorylates (energizes) transcription factors, so more messenger RNA for excitatory chemicals will result when p38 MAPK makes its appearance after pERK has brought it to life. Keep noting that phosphorylated kinases are bad news in Central Pain.
Are there any defenses? When intense noxious stimulation occurs in the dorsal horn, there is an increase in c-fos genes that increase dynorphin, an opium-like pain reducing substance in the central nervous system. As stated earlier, perhaps the slight protection by c-fos related dynorphin explains why in Central Pain touch has a delay for evoked pain, while touch causes pain instantly in peripheral nerve injury. Dynorphin is overcome by other factors, it would appear, provided it actually plays a role in slowing evoked pain from tactile stimulation in Central Pain.
NMDA does many things, including increasing calcium concentrations inside the nerve cell. NMDA also activates protein kinases (PKC), which in turn cause increased phosphorylation of receptors of excitatory proteins in the higher order neuron. The picture you need to keep in mind is that NMDA, when it kicks up the PKC is a major, major pain augmenter.
On top of the actions initiated by NMDA, there is also a MAPK-initiated cascade of events that dramatically increase pain. Increased calcium causes release from the membrane of phospholipaseA2 (PLA2), which activates arachidonic acid, a precursor of cyclo-oxygenase, which forms prostaglandin, one of the prostinoids we mentioned earlier that can excite the pain process. So now we have talked about prostaglandins acting at the peripheral end of the C-fibers to cause pain, and now we are talking about the same process occurring in the dorsal horn of the cord. Prostaglandins can operate on the EP receptors in second order neurons, which opens more calcium channels. So, you see how the pain cascade builds and builds.
Recent work by Tarek Samad and others surprised everyone by identifying the cytokine, interleukin 1-B (IL1B) in spinal cord fluid. The reason is that this cytokine leads to the formation of cyclooxygenase-2 (Cox-2) which helps form prostaglandin. This is the first evidence that the same process seems to be occurring at all three stages in the pain cycle. These stages are: the inflammatory process at the nerve ending in the skin, inside the cord where first order and second order neurons connect (although debate continues about the relative roles of the Cox-2 gene and c-Fos genes), and after Dr. Samad’s research, interleukin 1B and prostaglandin E appear to be active in the thalamus as well! There are genes that produce cyclooxygenase and the other pain chemicals, so regulation of genes is very important and more must be understood. Of course, this work only pertains to normal pain so far. None of this has been studied in Central Pain.
You’ll remember that cyclic AMP supercharges PKA. The cyclic AMP response element binding protein (CREB) is important in altering transcription. To act, CREB must be phosphorylated (energized) itself if it is at serine. Many enzymes such as PKA, PKC, and the Calcium/calmodulin kinases can accomplish phosphorylation of CREB. Malmberg has shown that strains of rats lacking the gamma isoform of PKC do not develop neuropathic pain. Electrical stimulation of C-fibers causes prolonged pCREB induction in the dorsal root ganglion nerve cells. (See work of Ru-Rong Ji).
We stated earlier that there is a dorsal root ganglion located just outside the spine, which is a collection of different types of nerves. Separate from the pain system described above is the sympathetic (or involuntary) nervous system. Pain afferents can travel in this system as well and converge from different neurons onto cell bodies in the sympathetic ganglion, which is virtually part of the dorsal root ganglion.
For the sake of simplicity, it is thought that the augmentation of the pain in Central Pain affected by fear, strong emotion, and threat travels along this sympathetic chain of neurons. Electrical transmissions, called evoked potentials, have been detected from the stellate ganglion of the sympathetic chain in the CM nucleus of the thalamus, a definite pain center. Not all Central Pain patients have this, but in those who do, it can be to such an extent that they have what is considered to be a sympathetically maintained component to their Central Pain. They may complain of increased pain, fear, and overreaction to noise, and to sudden interruption of the visual field, possibly related to the rear thalamus, the putamen. This is different, however, from reflex sympathetic dystrophy, (now called complex regional pain syndrome, or CRPS), which is an injury to peripheral sympathetic nerves.
Remember that most of the work of the brain and central nervous system is to inhibit, whether they are from pain or anything else. It has been demonstrated in animal models that simple loss of interneurons that respond to the inhibitory chemicals GABA or glycine (called GABAergic and glycinergic neurons) is sufficient to generate a constant severe pain state, through loss of inhibition. Some researchers feel that loss of GABA through nerve injury is a major cause of Central Pain.
Well, there you have it. You may not be a neuroscientist, but hopefully you are getting the picture that research is far from stagnant, and that the neuroscientists arenot stuck in the muck. They are making progress all the time and they are knocking on the door of pain. Even most of the scientists who disagree with some of the theories presented here are on the track of other promising research, and the ultimate proof will be who reaches the finish line first. The total elimination of needless pain will be realized. The single biggest obstacle is adequate funding for basic pain research, not lack of brainpower. There are already some brilliant minds available and ready to work on the problem.