As most people know by now, computers are binary. Classic joke: There are 10 kinds of people in the world, those who can speak binary and those who cannot. The transistors which make up computers are nothing but toggle switches. This is nothing to be ashamed of, since mankind itself is largely produced and maintained by the toggling genes, and the “noncoding” DNA which turns on “real” genes nearby, ie genes which make (code for) proteins.
The toggling is really messed up in Central Pain. Our Central Nervous System keeps trying to repair injured neurons in a way that causes genes (quite possibly in the microglia around the neurons) to pour out pain exciters in a dysregulated fashion. All hell has broken loose, or at least it has arrived prematurely.
The biggest story in biology for some people of late has been the realization that animals, including humans, only have about twenty five thousand genes, far less than was imagined. Furthermore, the genes which make proteins are uncomfortably similar no matter in which species they are found. There has to be more to the story. A hox gene (see below) in a fruit fly which produces an eye protein will not cause a rat to grow a fruit fly eye, even if the protein manufacturing gene is virtually the same. Correspondingly, a rat eye protein gene will not result in a rat eye in the fruit fly, if the eye protein gene from rats is used to replace the fruit fly gene. Consequently, the assembly of gene manufactured proteins requires another step for specificity in the animal. However, it is possible to trick this system and grow, for example, a nonfunctioning human ear on the back of a rat. It remains, however, a rat. Pain plays the role pain plays in rats, even when they are given Central Pain. Still, since virtually all species make the same cascade of pain chemicals, the examination of central pain in rats tells us a great deal about which proteins are amiss in the nervous system of humans.
This startling economy in Nature can be worked both ways, for and against classic evolution. Ninety five percent of our DNA is what is called “noncoding”, ie. it does NOT make any proteins. Basically, a gene is a length of DNA on some chromosome which makes a protein.
Long volumes have been written using only several thousand words. There are almost an unlimited number of combinations of these twenty five thousand genes to explain the diversity in biology. There will not be enough time for scientists to exploit every combination and permutation of these genes, but there will be an undoubted attempt to try to make new organisms, recreate extinct ones, and improve the ones that exist. The real secrets to the acts of “engineered creation” may lie in the noncoding DNA anyway. The genes and the proteins they make are not the final answer at all.
The genes are turned on and off during embryonic life in a scripted blueprint fashion that is so complex one cannot imagine it, including predetermined changes BY THE HOUR as the various structures form. Embryology, the forgotten science, is about to climb back on top of the heap. Biochmemists studying adults struggle to figure out how we do life, in a comparatively steady state. Embryologists must deal with life zipping past at high rates of change. Their job is like mapping an explosion.
What is important is the realization that ninety-five percent of our DNA is devoted to nothing but “toggling”.
It is not bulletproof, this toggling, and Central Pain is a good example of what happens when proteins are poured out without proper and helpful control.
What injures the control genes? Jeffrey Coull has been an author here at painonline, discussing the meaning of a peer reviewed paper on chloride carriers and central pain. Coull’s current blockbuster paper, reported recently at painonline.com and in Dec 15 05 Nature, shows that release of BDNF by microglia interferes with the binding of GABA-A with its receptor. Glia, or cells AROUND the neurons, come in several varieties, one of which is the microglia, the apparent source of BDNF, thought to be an attempt to cause injured nerves to repair themselves. An injured neuron is like a severely injured dog, who cannot be helped. The howling is so annoying, it might be better if the dog had died. GABA-A is how the body keeps pain neurons from becoming oversensitized. GABA-A is the balancer of glutamate. It is the yin for the yang of pain. In the brain, the exciter is aspartate and the quieter is glycine, but the principle is the same.
This action of BDNF, the preventing of GABA-A from binding with its receptor, effectively ends pain inhibition and destroys the balance between inhibition and excitation, a check and balance of damping on both sides that goes on throughout nearly all the nervous system, in both motor and sensory functions.
Togglers tell a protein making gene whether and when to turn on and off. Combinations of toggled proteins can act as graded implementers. At least this is the existing theory. This binary sort of behavior, even though it is “on” or “off” leads to unbelievably large numbers of possibilities. It also leads to varying degrees of severity of central pain and to different varieties of pain. Toggling paradigms are not random by a far stretch, as we know the rate of mutations and keep coming up against the problem that even if life has been here for fifteen billion years (which is far longer than anyone imagines and is the estimated age of the universe), it still is not long enough to account for the complexity which has evolved in many enzymes and proteins.
Hence, the debate between raw godless evolution and intelligent design continues to this day. Is a Being so intelligent that He could deposit a library of genes on earth which would play out into humans less or more magnificent than one whose attention is constanty required to make sure things turn out all right.
If other worlds are populated, is it not possible that intelligent beings might have a few surprising twists in their nature compared to how mankind exists here on earth. Regardless, where does pain come in. What function does it play. Protection and aversive learning seem logical. What then, is going on in Central Pain?
What we call pain is a very elaborate process, with large amounts of brain space devoted to it, and an array of chemicals so numerous and subtle, it can take a life to learn, let alone to understand. Nature did not short mankind in providing for pain–it must therefore be an important thing. It is so well integrated that nothing else compares to it. Pain is so direct, that for hundreds of years science assumed it would be a simple mechanism. In fact, its clarity requires a huge amount of resources to be devoted to pain so we get a clear message. Our survival depends on knowing what is happening.
It would appear, however, that somehow in nerve injury, the toggle genes, some of which are called Hox genes (so called “toolbox genes” which are more commonly associated with embryological events) are dysfunctional. Fetal ion channels are for fetuses, but somehow those with Central Pain are plastered with them all through the dorsal root ganglion, making the DRG pain fibers extremely hypersensitized, so much so that occlusive touch (thermal effects) or a cold blast can send the patient into agony.
Proteins which are clearly excitatory of pain begin to pour out in CP. Channels with careful controls lose their control apparatus. Elsewhere at this site is a review of the startling new work by Coull et al which shows that chloride and other anions, which are normally inhibitory of pain in the nervous system, cannot perform this function because the release of a protein, BDNF, interferes with the binding of GABA-A, the pain inhibitory chemical which keeps things in check, with its receptor, trkB.
There can be no doubt that if a building has both heating and air conditioning and the air conditioner is converted to another furnace, the building is going to get REALLY hot. This is analogous to what is going on in Central Pain. The anions, the inhibitors, which are the normal protection against too much sensitization toward pain. go into a reversal, called “anion reversal”, where the ordinarily inhibitory signal of anions is converted into an excitatory action potential. This turns day into night where pain is concerned. Understanding the chemical implications of this gross and altering process makes clear why those with Central Pain cannot stand light touch.
The stimulus of touch from clothing, for example, would normally have little significance, and usually never reach consciousness because anions would keep it in perspective. When they fail, light touch becomes as significant as a branding iron. We use the word “hypersensitized” here, but that does not begin to cover it. Central Pain has been frequently cited as the most severe chronic pain state known to man. That bears reflection and repetition. When it is considered that opiates normally have no effect on CP, it is easy to see why they do not take a back seat to anyone, including those dying of cancer, since opiates DO have an effect in cancer pain.
It is hard to imagine a situation which would be worse, when the inhibitory apparatus is converted to an engine of pain. Those with Central Pain have always been amazed at the experience, so amazed that it feels like the universe does not make sense any more, which in fact it does not, to them.
It is “insane” for light touch to cause burning pain, but it is not insane for the brain to read excitatory pain signal as pain. In fact, it is quite sane, and unfortunately unavoidable. While the evolutionary development (some like to call their discipline “evo-devo”) people gear up, we hope they will not fail to look at the pain apparatus, the chemicals and proteins which are produced almost universally among life forms, and how genetic manipulations can be performed to turn off the pain apparatus, or at least dampen it.
Until the garden variety scientist catches up to the pain scientists there will still be plenty of doubters and skeptics. But the flood of MAPK, acififying acids, and cytokines pouring out into the dorsal root ganglion is a sort of horrifying event. It is torture at the molecular level. It is the injection of a fluid which will reduce the strongest to ashes in a short time. It is surprising that Nature did not produce animals resistant to such an event, but it did not. What is fortunate is that it did produce humans intelligent enough to shut it off. That means research and research requires money and effort.
No more than a handful of top pain researchers exist in the U.S. However, nature abhors a vacuum. Since many other fields of science have been gone through, the brain is just now beginning to catch the interest of those who wish to publish and make their mark. We are fortunate that pain is a fertile area, since it is so easy to study, but has not yet been studied. What more could a PhD candidate desire. We look for good things in the near future. Hang on. Central Pain has come out of the closet.