The Swedish, always very good in pain theory, have suggested that excess calcium allowed across the blood brain barrier by the action of Substance P and CGRP actually induces excessive pain synapses to form by causing glia to release factors which increase the number of synapses, which in turn increases calcium flow, etc. etc.. If true, it means the pipes for sending out pain could multiply and stay multiplied.
Although many of the individual steps in chronic pain have been worked out, ie. calcium pours into the synaptic gap, then calcium activates chemicals which activate NMDA, which then tries to take you apart (usually successfully), etc, what isn’t known is how all these things fit together. There are some rather large gaps in theory and scientists know it. How exactly does the calcium fit into neuroinflammation.
Now, E. Hansson (see Acta Physiol (Oxf). 2006 May;187(1-2):321-7) has theorized that Substance P and CGRP (calcitonin gene related peptide) pour into the synapse at the time of nerve injury. These two substances alter the blood brain barrier, allowing calcium to insult the glia around the neurons. Normally the cells which line the blood vessels penetrating the brain are so tightly joined that nothing much can infuse out into the brain. This is called the blood/brain barrier.
It is already known that CGRP DOES alter the Blood/Brain barrier during migraine. Substance P can do this also. The result is more metallic ions able to pass the BB barrier, which changes the delicate balance of brain chemicals. The glia in turn release chemicals which cause many more synapses or connections to form, by which the pain signal can be amplified, PERMANENTLY. (Not our idea of a good time). Glia are inflammatory like cells which reside around neurons. Hansson, who lives in Goteborg, may be on the right track. His ideas account for growth factors, transcription factors, etc.
Anyone who makes a theory about CP has to account for the obvious, that calcium is running amok. Calcium in sufficient quantity can kill a cell, melt the membranes of mitochondria and do other decidedly bad things to nerves. One positive for Hansson’s theory is that any explanation of central pain has to account for the fact that the burning is always much worse distally. Dr. Patrick Wall used to say that the distality of central pain means “cellularity” and “synaptivity”. This actually was a theory we worked out together. “Distality means cellularity and synaptivity”. In other words, the only reasonable explanation for the marked increase in dysesthetic burning distally in CP is the greater number of neurons devoted to distal areas in the thalamus and sensory cortex. Fingertips and toes have many more connections to the somatosensory cortex (SI) than say the middle of the back. More hypersensitized neurons means more pain. Distal neurons are also well connected, being at the top of the hierarchy of sensation that the brain honors.
Thus, when the neurons can do nothing but burn, the lips, fingertips and toes burn much more. The greater numbers of neurons could be expected to form that many more multiplied synapses trafficking upcoming pain signals which hit the connection areas (cord, thalamus etc) and feed into other neurons at the synaptic gap. In an atom bomb, a little explosion releases a really big explosion. Central Pain is the same way, action potentials multiply horrifically as they pass via the thalamus to the cortical regions of the brain which encode pain.
What Hansson is not willing to say is whether the increased permeability of the blood brain barrier, (the abnormally gaped endothelial cells of the brain microvasculature), allowing damage to the glia, comes from waves or “oscillations” of calcium, due to physiologic mechanisms, or whether things are more random, which is to say due to calcium overloads which periodically occur, the so called calcium “transients”. He does not know whether Calcium is behaving as a loose cannon (transients) or whether the waves of calcium which occur naturally (oscillations) overpower the pain system.
As you know from reading here, the-N type calcium channels are the active ones in pain nerves. Calcium also powers up the TRPV-1 channel, which is just another calcium channel for C fibers. This makes TRPV-1 hugely important. The “transient receptor potential vanilloid 1″ receptor is the target of resiniferatoxin, the purified sap of the Euphorbia cactus.
The Swedes were the first to develop an animal model for Central Pain (presensitization with Erythrocin B followed by lasering of the cord) and the scientists at Karolinska are as good as anyone in the world. At many conferences their work is really the predominant science presented, with the Americans embarassingly overrepresented by those who talk about placebo effect. Many of these are experts on pain by virtue of having had some pretty fierce toothaches in their day combined with a teaching position in some behavioral science department. Tony Yaksh and the Willis/Hulsebosch progeny usually save the day for us, along with a lot of other scientists who work here but whose nation of origin is NOT the United States. It is hard for Americans to realize foreign scientists are often far superior, but then, they have forgotten Einstein, Niels Bohr, Fleming, and people like that. Foreigners may not play American Football as well (although they are getting quite good at basketball), but frankly, most of the research in basic pain chemistry is done by foreigners, except for some Texans who for some reason tend to win the Tour de France and also be good at pain chemistry.
Americans are tough and know from watching rodeo on TV that pain is all psychological–cowboy science. Americans were raised on the heroics of “rugged individualism”, a romantic myth which vanished around the time Teddy Roosevelt died. The idea humans are supposed to suffer also permeates our churches (Medievalism never really died out–it just took on a new country) and of course indifference to pain is the hallmark of our health care nonsystem, which is regulated by federal bureaucrats whose jobs depend on opiates being REALLY, REALLY dangerous, but not dangerous ENOUGH to allocate money to study pain.
Jorgen Boivie at Karolinska, another Swede, has contributed information to painonline from an early point. Any theory by Hansson must also explain Boivie’s Paradox, which is that “One must loose sensation in order to become a candidate for more severe pain (CP).” This rule derived from Dejerine and Roussy in 1906, who found that areas of intense burning always were the most impaired as to light touch, with the dysesthetic burning being exacerbated by light touch. It is a paradox indeed. The nerves are trying to compensate for the lousy job they do with light touch by overdoing it with pain from light touch.
There is an exchange of sodium and calcium (Na+ and Ca++) at the neuronal membrane, which winds up causing an excess of calcium when the nerve is injured. Hansson’s theory of calcium waves could also explain why touch is altered. The neurons of touch are injured and cannot function normally, because an original injury altered the vascular permeability of the BB barrier enough to hypersensitize EVERY synapse. Increasing synapses is also known as brain plasticity.
The pieces of this mystery are being assembled. Scientists are trying to put the Chinese puzzle together. There may still be a few missing pieces, but everything right now is pointing to neuroinflammation. The body attacks inflammatory matter, whether bacteriological or chemical with degrading chemicals, which are or can be thought of as the equivalent of acids. As you all know, CP dysesthesia is perceived as an “acid burn”. It’s not about attitude, it’s about acid.
The rest of the world can buy our operating systems, and then we will turn around and give it all back one day by buying their pain treatments.