How Much is Too Much?

We are twice as bad off as we were before spinal cord injury; or, is it a thousand times worse? It all depends.

“Glia” or more properly “Neuroglia” are small cells which surround neurons in the central nervous system at a ratio of 5:1. Some scientists believe that glia are even capable of causing other cells to turn INTO neurons. Glia make the chemicals which regulate what the neuron is doing genetically. The genes, tiny protein factories, are not on automatic pilots. They listen to instructions. Like any machine, a neuron can do bad things if the direction signals turn into chaos. They can become like the mythical Hollywood robot, which has a glitch in programming and attempts to destroy everyone on the space ship. Some good dramas have come out of the contest between the crew to kill the robot before it can kill them.

Glia do just the opposite. When they realize an injured neuron is “not perfect”, they pour out a concoction of growth factors to try to repair the neuron. Unfortuantely, these growth factors have a side effect They may affect the little factories making pain exciters. Then, the show is over. Life is nearly over. Severe central pain sets in. This is the worst pain state known to man. It is beyond and outside language. It may make you wish the glia DID kill the organism, rather than attempting to repair it. For the most accurate description, see the picture drawn by Karen Musick, who herself has CP, at the home page.

At the very least, they produce the growth factors and kinases which upregulate or downregulate neurons, as well as producing the growth factors which influence neuronal attempts at repair. At this site you will find many articles concerning BDNF, TNF, and other growth factors related to the production of central pain, stemming from the determination of glia to get the neurons going again. Central Pain can be viewed as the glia beating a dead horse (the injured neuron).

Some day, when we learn to manipulate growth factors into cord repair, we will be thankful for the efforts of the glia to whip the neurons into a frenzy of activity. Right now though, they are destroying our lives. Some very important things, such as blood, are necessary in the body, but do considerable harm when they leak into areas where they do not belong. Nerve growth factors are aimed at repair, but their role is clearly destructive when it comes to freedom from pain.

Detloff et al publishing in J Neurol Phys Ther. 2006 Dec;30(4):201-8.CSM 2007 “Spinal Cord Injury: GLIAL ACTIVATION AND THE PRODUCTION OF PROINFLAMMATORY CYTOKINES PREDICTS THE DEVELOPMENT OF NEUROPATHIC PAIN AFTER SPINAL CORD INJURY” have raised some interesting questions about how much glial excitation is necessary to develop nerve injury pain. Apparently not very much.

Doubling the rate of glial PX24 which is activated by ATP (see prior articles here giving more detail on ionotropic ATP) is enough to cause central pain.

A two hundred percent increase seems out of proportion to the agony of burning dysesthesia. Light touch of the distal extremeties can make life unbearable. Spontaneous burning requires no stimulation at all. This seems degrees of order above doubling as to pain severity.

Since the increase in pain experienced in CP is exponential, translating perhaps into a factor of 50 to 100 times the pain sensitivity of a normal person, glial pain excitation must have potent results. Somewhere along the line, multipliers also likely are at work. This could be in the “on the fly” software sent to the cortex attached to a pain signal, in the inherent pattern of thalamo-cortical or cortico-cortical processing of signals; or, in the known failure of inhibition in CP.

These authors also measured p38 (meaning p38 Mitogen Activated Protein Kinase) as well as interleukins 1 and 6.

Glial cells include within them the smaller group known as oligodendrocytes. The discovery by Bhat in Neuurochem Research Jan 2007 that p38 MAPK inhibits differentiation of oligodendrocytes tells us that p38 is really a nerve growth factor.

Detloff injected acid or performed mild spinal cord displacement to induce central pain (tactile mechanical allodynia measured with von Frey hairs, thermal allodynia with hotplate) and then studied Tumor Necrosis Factor, Interleukin-1 and interleukin-6, which are all proinflammatory cytokines. (You will recall that existing theory on central pain views it as chronic neuroinflammation of the pain system). It is interesting how many animal models there are now for central pain and how many events are able to precipitate it. Here, even mild displacement (0.5 mm) of the cord achieved the result. We have a laser injury model, a mechanical drop model (falling rod), injection of acid model, and a cord displacement model, all of which are capable of producing an animal with central pain. This is surprising considering that twenty years ago, not one neurologist in a hundred knew what central pain was, and the word “central pain” did not even appear in the leading neurology textbook, nor most others.

The really big impetus seems to have come after the realization that p38 MAPK, being proinflammatory, can create a chemical situation harmful to the blood vessels and fibers of the heart. Cardiologists are not at the stage of questioning whether heart attacks exist. This gives them an advantage over the neurosurgeons, who are still not quite sure about the reality of central pain. It has been a long road even to get the brain wizards to recognize the invisible. Now that they call CP sufferers “poor bastards”, it at least affords CP subjects the dignity of being a a real patient. Next, we would like them to cure the miserable condition. Minds change slowly. Things take time. Too bad.

Many have died and more have lived out their lives in unbearable agony because the unseen was imagined not to exist. This is not unlike the attempts of Semmelweiss to convince those attending childbirth to wash their hands, because germs really did exist, even if they were unseen. Pain chemicals, of course, are still not “seen”, but they can be detected through appropriate chemical analysis. All that can be seen are the little rats trying to chew their neuropathic legs off.

It took a long time for this rat behavior to translate into an awareness that humans with the same condition might be in unspeakably bad shape. Our heads bow in gratitude at the early doctors who recognized CP for what it was and assessed it to be the terrible enemy of mankind which it is. Who can sufficiently praise S. Weir Mitchell, John Dejerine, Gustave Roussy, George Riddoch, Patrick Wall, John Bonica, Wm Willis Jr., and the others who tried to declaim against central pain like early liberationists protested against slavery. Without these early doctors, we would not have the brilliant scientists of today who are on the hunt for a cure for nerve injury pain.

Like much of progress, advancements have had to come over the dead body of false religion, the unfortunate idea that God WANTS us to suffer. Some are still like the primitives who see God as a killer, appeased only by the sacrifice of young virgins, capriciously meting out blood and horror on the human race. Rightfully, such a being would be called a “devil”, but so many prefer to see God this way–the most threatening entity in the universe. Is it not blasphemous to speak of the God of love in this fashion? If so, there is a lot of blasphemy going on, not least from the pulpit. Cotton Mather type religion is alive and well today, and just as prone to creating witch hunts as it was back in his day. When we get too righteous and start “aiming beyond the mark”, really bad things happen. We start killing those we do not understand. Fearing God helps us repent. But we are commanded to get to the point where we love Him, as He loves us, by serving our fellow man. No one serves their fellow man better than pain resarchers. Remnants of the old ignorance are still with us. The disease will be cured before the majority of the medical profession gets around to realizing that Central Pain exists.

Using messenger RNA to study gene upregulation, Detloff et al found that “A cut-off of 200% microglial activation accurately predicted allodynia…” This is astounding. The authors took the pains to MEASURE and came up with a puny doubling turning the poor little experimental rats into the pained creatures of CP.

Doubling is not very much activation, but from the experience of CP patients, what a difference it makes. If we turn the radio twice as loud it may be a little painful, but how a doubling of glial activity can be amplified into the terror we know as central pain is not clear.

There is a temporal shift in chemical pain maintenance, as well. TNF alpha and interleukin-1 hit highs at 7-35 days and then disappear. Interleukin-6 then comes on, perhaps to maintain the nerve injury state. There is so much to learn and so much which needs to be studied about pain. Few of the prior studies bothered to calculate QUANTITIES of chemical pain exciters, and even fewer did sequential measurements day by day to study the temporal development of nerve injury pain. It is easy to find topics that need studying. The money to fund these studies is the problem.

In the meantime, if your glia are twice as active as normal, you have our deepest sympathy. These authors termed the cord trauma “moderate” but the pain was termed “high grade”. If you are one of those patients whose doctors have been skeptical because your injury is not so severe but your pain is a killer, you can show them this study. Not that they are likely to know what p38 MAPK is, but then, maybe they will fake it long enough to dial up the literature and inform themselves.