Sometimes the use of the big chemical terms can mask some rather simple discussions of mechanisms of nerve injury pain. The reader should attempt to bypass intimidating chemical names to understand what is really being suggested.
The readership at the chemical pages here indicates that many readers do not feel capable of understanding the technical discussions. This is understandable. However, we hope the discussion of what is going on in nerve injury pain will not be limited to the handful of biochemists who do the benchtop work. Therefore, we attempt some analogies here which may make things easier to grasp. And we are all for simplicity.
Currently, the debate over the cause of nerve injury pain centers around two ideas. Both may be correct. They are not mutually exclusive.
One idea is that Central Pain is simply a failure of injured nerve cells to manufacture chemicals in the proper amounts. This is known to be true for the inhibitory currents, due to failure of injured neurons to manufacture the protein, KCC2, which carries the chloride ion to the cell membrane, chloride ion being necessary to craft inhibitory signal. This failure converts inhibitory message to excitatory pain signals going to the brain. KCC2 insufficiency means chloride failure and chloride failure means failure of inhibition of pain. This creates a positive feedback in pain since any attempt to inhibit pain results in more excitation which makes it worse. (see J.Coull elsewhere at this site)
The second idea goes under the broad term, “exciter toxicity”. This means that genetic protein factories, present in the chromosomes of damaged cells, sense the nerve injury, but in attempting repair, fail to do it right. The nerve growth factors pour out too many precursors for the manufacture of pain chemicals, which go under the broad name of the ERK cascade of chemicals. ERK chemicals (see elsewhere at this site) tend to be acidifying and cause a response in the VR-1 calcium channel (now known as the TRPV-1 channel), which excites the pain signal, Making this worse is the production of abnormal fetal channels by the imbalanced nerve growth repair, the fetal Nav1.3 Sodium channels, which appear to mediate nerve injury pain. By contrast, Nav1.8 is the channel for normal, neurotypical pain.
Certain chemical steps must be more vulnerable, since nearly identical central pains can be seen in cord injury, multiple sclerosis, tumor infiltration, viral disease/toxins, scarring (arachnoiditis) and syringomyelia.
With nerve injury, the weakest links are the first to go, and the burning remains. At least one researcher has called it the brain’s way of using the body against itself, in order to retain contact with the exterior environment. Others have called it a big price to pay for information that is mostly trivial but occasionally very important. Nature abhors a vacuum.
Those born with no pain sense still can feel touch, but they die from joint infections, secondary to not knowing when they are in a bad position for the joints.
As you can see, these ideas encompass quite a bit of theory. The articles you read can often be placed under one or both of these theories. The solid evidence indicates that both theories are correct.
What is needed then, are drugs which extinguish damaged cells, or at least prevent their causing a pain signal. The idea that stem cells could replace some of the KCC2 or other deficient chemicals, causes considerable interest.
Pain is normally a signal creating awareness of some injury occurring in the body. With nerve injury pain, the abnormal production of channels and ERK chemicals, creates an agonizing burning. Because this signal is not well integrated, and chemically incomplete, there is a good deal of signal which does not follow the normal sequences of chemical events, and creates “short circuits” in the pain system, which cause a bizarre sensation of burning. This has been compared to putting tinfoil in the microwave. The heating still occurs, but it is uncontrolled, resulting in sparking and results that reflect heating energy, but do not behave as they should.
The burning, known formerly as protopathic pain, was shown by Hardy in the 1940′s to be the last pain to stop functioning in a compromised pain nerve. He put a cuff around the arm to constrict blood flow and watched how the pain sensation changed as the nerve failed.
The most durable pain was the protopathic burning. This same pain is what is present in central pain, due to nerve injury. Central Pain usually first occurs when recovery from spinal shock reveals the injury to be incomplete. As some other function returns, the burning pain appears. The obvious conclusion is that the nerve is not completely well, but is limping along as best it can, driven to repair itself by nerve growth/repair factors, but unable to restore the ordinary order of pain events. The confusion, like sparking of tinfoil in the microwave suggests something terrible, is read as full out pain, by the brain.
We now have chemical descriptions of just HOW the nerve is not doing well. These nerves do not operate chemically in the same fashion as a fully functional nerve. They display primarily the most durable pain, with a mix of other unpleasant sensations thrown in. We call this Central Pain. The injury travels to the central brain parts, such as the thalamus, where the more peripheral injury induces central change.
The most widely held interpretation of this is that the brain, deprived of a full, normal signal, increases the gain to the point that pain is felt ALL THE TIME, without any stimulus or ongoing injury being present to account for the pain. The chemicals responsible for this hypersenstivity in the cord have been mostly identified. The specific way the brain increases gain has not been elucidated, but appears to mirror hypersensitivity in the cord, since the same acidifying chemicals appear. (see at this site, Tarek Samad’s finding of leukotrienes in the thalamux, in nerve injury).