To understand the pain of fibromyalgia you have to be introduced to two rather important aspects of pain biology — central sensitization and descending inhibition. These are actual changes in the central nervous system that affect how people appreciate sensations that are painful — remember one of the keys in understanding FMS is that what is painful to one person may not be painful to another. These three short reports will enter into some rather technical neurobiology (the study of the biology of the nervous system) but it's important material if you really want to understand just how the pain of FMS differs from the pain of other diseases.
To be succinct, the pain of FMS results from permanent neural plasticity changes creating a state of central sensitization maintained by peripheral painful input with impairment in descending pain modulation. Wow!
You'll know what that means when you finish reading the series of three articles on the Pain is in the Brain of FMS. To translate that now: Neural plasticity means nervous system flexibility, even though it sounds rather awkward to say permanent nervous system flexibility. What that statement implies is that the ability of the nervous system to change, which is usually a good thing, has in the case of FMS been put to a bad use. For example, when you first learn to play a musical instrument you are not very proficient and it doesn’t sound very good, but as you practice and improve you notice how much better you become. Because of the plasticity, or flexibility, of your nervous system, new nervous system pathways are created. You learn to read music and your fingers are able to find the keys of a piano or the strings of a guitar more quickly and with more fluid motions. The more you practice, the more engrained those pathways become, almost like a trail through the woods becomes more apparent as it is used more. In FMS, that same flexibility has been not used appropriately.
First we have to talk about central sensitization and descending inhibition. We’re going to begin a fascinating journey that starts in the periphery of the body when the pain nerves sense something noxious or painful and carry that sensation into the spinal cord. There, they begin to irritate a special nerve cell which begins a process called windup. This starts changes that will result in signals being sent to the brain that result in central sensitization, an amplification of both normal pain signals into abnormally painful signals and an amplification of what isn’t usually painful into sensations that are perceived as painful (this latter phenomenon is termed allodynia). In normal individuals this process would also activate a system called descending inhibition that begins in the brain and would travel back into the spinal cord to dampen the potentially up-coming pain signals before they reached the brain. However, in FMS patients this descending system doesn’t work. Read on to find out more details.
As we said above, in order to understand central sensitization, we’re going to have to think about what goes on in the spinal cord. But before we start in the spinal cord you should know a little about the way pain sensations get into the spinal cord – the types of pain nerves. There are two main types of pain nerves; they’re called A-delta and C-fibers. They have their sensory endings in the periphery of the body, for instance the skin or muscle and carry perceptions into the spinal cord. The A-delta nerves can conduct a nerve impulse rather rapidly, 12 to 30 meters per second. They transmit acute pain that may trigger withdrawal reactions, for instance the pain you may feel if you pick up a hot plate and then have a withdrawal reaction where suddenly you open your hand to drop it. There are two types of A-delta nerves. One type responds to mechanical pain while the other type responds to temperature or chemical stimulation.
The other type of fiber, the C-fiber, is a slow conducting nerve, 1.6 meters per second, and is termed a polymodal receptor. They can respond to mechanical, thermal, and chemical stimulation and are also specific for chemicals that are released during tissue injury, such as potassium ions, the chemicals acetylcholine, serotonin, the pain chemical substance P, and histamine. C-fibers basically cover most of the territory when it comes to transmitting pain signals.
There is another type of nerve fiber you should also know about, it is called the A-beta fiber. These are very fast conducting, 30 to 100 meters per second, low threshold mechanical nerve fibers – low threshold meaning it doesn’t take much mechanical stimulation to get these guys stimulated. They come with specialized receptor endings. The specialized receptors allow them to be able to sense specific things about muscles – how fast they are moving, how contracted they are, etc. which your brain uses to essentially get an idea about the three-dimensional position of your body.
What also makes all these nerves special is not so much what type of information they transmit but where they go in the spinal cord. There are distinct layers in the spinal cord that have numbers and names. A-delta and C-fibers will go from the peripheral tissues and end primarily in lamina I (the marginal zone) and lamina II (the substantia gelatinosa) in the spinal cord. The latter is the site of action of opioid pain medications in the spinal cord and other pain medications such as clonidine.
Possibly the most important place that the A-delta and C-fibers can go is to lamina V. Lamina V is the home of a very special group of nerve cells called “wide-dynamic range neurons,” or WDRNs. These neurons are so important you could go up to any pain physician, neurologist, or FMS researcher and ask them what “WDRN” stands for and they will be able to tell you – everybody knows about them. Their name gives away their secret – they respond to wide range of inputs. They can respond to an extensive range of peripheral innocuous (slight tactile) or painful stimuli (intense mechanical or thermal stimulation). They are the key to central sensitization as they are the first step in the process.
It was in a simple two page paper published in 1965 that two very famous pain researchers, Drs. Mendell and Wall demonstrated that if WDRNs receive repetitive stimulation from C-fibers something unusual happens. The WDRNs become increasingly more excited – they “windup.” However, the stimulation that the C-fiber nerves provide has to be just a certain frequency. The C-fibers have to stimulate the WDRNs at least three times per second, or 0.3 Hz. The frequency of 0.3 Hz evidently corresponds to the natural discharge frequency of C-fibers responding to stimuli that are felt as slightly painful. The WDRNs also receive inputs from the A-delta pain nerves and the A-beta nerves (the muscle nerves).
Now that we’ve introduced wind-up, time to talk about specifically just how that happens, but we need to introduce a few more new terms. There are two very important receptors on the surface of the WDRN. Receptors are like the key holes into which specific neurotransmitters can fit, causing changes in the cell. These two receptors are known by their abbreviations –AMPA and NMDA. The reason they are always known by their abbreviations is because their full names are simply too long to write out all the time: AMPA is alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid and NMDA is N-methyl-D-aspartate.
The AMPA receptors are the major receptors that mediate pain in the central nervous system. They respond to the most common pain neurotransmitter in the spinal cord, a chemical called glutamate. These receptors open and close quickly so the WDRN is stimulated rapidly – it doesn’t have time to wind-up. Under these conditions, the NMDA receptor just sits quietly in the neuron’s membrane and doesn’t do anything, you could say it is just minding its own business. When the frequency of stimulation exceeds 0.3 Hz (i.e. more than three times per second) the release from the primary nerve pain C fibers of glutamate and another neurotransmitter called substance P starts to activates enough AMPA receptors and the receptors for substance P, which are known as the neurokinin-1 receptors, so that things begin to change. There are sufficient changes to stimulate the WDRN’s NMDA receptors and begin the process of wind-up. It is the NMDA receptor that is primarily responsible for wind-up.
You may have read about some medications being "NMDA-antagonists," meaning they block the action of NMDA receptors. Methadone, ketamine, and dextromethorphan have NMDA antagonistic action. This is the same NMDA receptor that is being talked about. NMDA receptors are found elsewhere in the nervous system and play an important role in other aspects of pain processing which you will read about in future short reports about medications used in FMS. Many pain researchers feel the NMDA receptor is one of the most important pain receptors in the central nervous system. It also has a role in memory and learning and in the mechanisms of addiction.
That the NMDA receptor is involved in the pain of FMS was first suggested in 1995 by a group of researchers who showed that an intravenous infusion of ketamine, an NMDA blocker, resulted in significant reductions in the pain intensity reported by FMS patients. Four later studies by their group confirmed that activation of NMDA receptors is involved in FMS pain. Other researchers were able to demonstrate that ketamine reduced muscle pain, wind-up, intense muscular pain, and referred pain from three widely distributed tender points – knee, epicondyle, and trapezius. Similar results were seen with another NMDA blocker, dextromethorphan.
A change that occurs as a result of the activation of the WDRN is an increase in the cell of the calcium ion. Overall, increases within a neuron of calcium are not a good thing. The rise in intracellular calcium in the WDRN makes an enzyme called nitric oxide synthase which produces a chemical called nitric oxide. Nitric oxide has a role in accelerating the pathway to central sensitization through ways that are still being elucidated. A group of FMS researchers have shown in FMS patients the pain from tender points matched changes with arginine, which is the chemical that is made into nitric oxide, with increases in the tender point index matching the increase in concentrations of arginine. Other researchers have shown a significant correlation between serum nitric oxide synthase and pain as well as higher nitric oxide synthase activity levels in FMS subjects with a history of migraine, pain, and morning stiffness.
Although substance P is widespread throughout the nervous system it is most concentrated in the C-fiber pain nerves. Substance P is rather special. It is one of the most “irritating” chemicals to WDRNs. When it binds to its receptor it causes long lasting changes to the WDRN. There is also in the spinal cord what are called “silent” synapses or connections between cells in the nervous system. The body seems to keep these in reserve for “emergencies.” One type of emergency is pain. Substance P calls these into action. Substance P can also diffuse through the spinal cord and activate other WDRNs. Reading this, you can equate substance P to the Paul Revere of pain chemicals.
Increased cerebrospinal fluid (CSF) levels of substance P were first investigated in FMS in 1988 as a factor in Raynaud’s phenomenon where levels four times normal were measured. Several later studies have shown levels up to three times normal levels of substance P in FMS. Raynaud’s is not infrequent in FMS. It is a medical condition where the fingers and toes become blue due to an abnormal constriction of the small blood vessels in the tips of each of these digits which shuts down the flow of oxygen to tissues causing the bluish colour. It is a hyper-excitation of the sympathetic nervous system, which controls the constriction of blood vessels and in many cases, occurs for unknown reasons although it can be brought on by cold or stress. Although no correlation to Raynaud’s was seen at that time substance P was proposed as a potential causative factor and diagnostic marker for FMS. One thing is for sure, these high levels of substance P means there is a substantial amount of activation of the C-fiber pain nerves.
Chronic fatigue syndrome and FMS have been considered from neighbors to twins, depending on who is doing the arguing. However, a very distinctive difference was noted in 1998, albeit in a small sample – all CSF values of substance P in a sample of CFS patients were within normal range. Since then, no study has been published showing anything different. This may be why CFS is not marked by excessive pain as is FMS.
Along with decreased pain thresholds, elevated levels of substance P have been associated with sleep disturbances, depression, and decreased production of cortisol. If you’d like to know more about cortisol, read the short reports on Cytokines and the Neuroendocrine Theories Behind FMS. There have also been some fascinating studies using laboratory animals. In mice, substance P was injected into the ventricles, which are the CSF containing areas of their brains, so that it could literally bathe the brain. When this was done, the mice had sleep disturbances – they couldn’t fall asleep and they woke up a lot. This finding has suggested that substance P may play a role in the sleep disturbances seen in FMS.
There is another chemical called nerve growth factor (NGF). When NGF is elevated it stimulates the production of substance P in the C-fiber nerves. Elevated NGF has also been noted in the CSF of FMS. Although the NGF concentrations varied considerably, interestingly significant levels have been found only in primary FMS patients, not in individuals with secondary FMS and nobody seems to know why. If you have read the section on the Radiological Imaging Studies of FMS – Part 2, in the second paragraph it mentions FMS patients experienced loss of brain matter. NGF has been implicated as being possibly responsible for casing this condition.
NGF is thought to be so important by one noted FMS research, Dr. Martinez-Lavin, that he has suggested that the elevated NGF levels may act in combination with trauma or infection to actually be responsible for FMS itself. There is a particular channel or tunnel on nerve cells that allows sodium to enter the cells which causes them to be activated. It is one of nine different types of sodium channels and its name is Nav1.7. NGF causes more of this particular sodium channel to be made by the cell and live on its membrane. When this happens the nerve cell is more easily excited and the ability to generate windup is greatly increased. Dr. Martinez-Lavin proposes that certain individuals may be at risk by having a genetic alteration in these channels which makes them more susceptible to developing FMS following any event that incites a strong inflammatory response, e.g., infection or whiplash injury. This is an interesting theory as it suggests that one simple channel can essentially be responsible for creating the syndrome of FMS. So far, his theory has not yet been proven.
There are other chemicals that contribute to windup. These are called calcitonin-G related peptide and brain-derived neurotrophic factor made by the pain nerves and released if the pain nerves are stimulated. Do you think they have been found to be increased in the CSF of FMS patients? If you answered yes, you would be correct.
Now that you know a little bit about windup you may be thinking this is certainly not a good thing for FMS patients, or any patient with pain. Well, unfortunately there is some bad news for FMS patients regarding windup. You’ll have to read Part 2 of the Pain in the Brain of FMS to find out what that is.