Glutamate and aspartate are the main excitatory neurotransmitters in the nervous system. GABA(A) and glycine are the primary two inhibitory amino acids of the nervous system. The receptor for glycine behaves oddly during development. Glycine is the double agent employed by both NMDA and inhibitory forces. Glycine is the mole in the NMDA organization. We are not presently exploiting the mole–somehow solving pain has not caught the imagination of anyone. It is, it would appear, OUR problem, and no concern of anyone else (except people like Christopher Reeve). Consequently, we are entirely too dependent on non-U.S. research for information on these topics.
Neuroprotection appears to be a very big deal in the body. The chronic pain system, based on N methyl D aspartate (NMDA) cannot work unless it has a coagonist, glycine. But wait a minute! Glycine is an inhibitor. Nitric oxide seems able to generate reactive oxygen species which would pose a threat to delicate nerves. NO attaches to NMDA and helps it along. So why did Nature place glycine right in the middle of the bad boys, right where it could disrupt the whole pain exciter process. Cleverly, glycine has the markings of a bad boy itself and acts as one early during embryonic development. But it has a change of heart somewhere along the line and decides it would rather help us out than hurt us.
Recalling that glutamate, a pain exciter, is inhibited by its chemical half brother, GABA, possibly via competitive inhibition of some sort, it will not be too surprising to learn that the receptor for glycine (which is an NMDA partner or coagonist), although it enables NMDA to forge ahead, also creates a weak link. Glycine in children and adults winds up inhibiting pain signal.
Glycine seems to outrank Nitric Oxide (NO) which is a neurotransmitter capable of helping pain develop. Those in the survey who have central pain in the trigeminal nerve branch which supplies the dura have reported severe headache from Viagra. This would be consistent with NO as a pain neurotransmitter since it is NO which Viagra promotes. Cialis, which comes on slower is much less likely to cause a dural headache in high CP.
Most substances do not work alone in the body. In the nervous system, many channels require that a neurotransmitter be connected via a ligand. Look at a ligand as an adapter. The glycine receptor is made up of two subunits, alpha and beta, in a 3:2 ratio of which only the alpha can tie via a ligand to channels, but the beta subunit does affect channel activity. The glycine beta subunit also uses a ligand to control the channels which are being inhibited, but the beta unit is more about placement of the inhibitory channels in the synaptic membrane.
Expanding on this, a ligand is a connector which one molecule uses to hook up one or more other molecules. The beta subunit causes the glycine receptors to gather in concentrated domains of the cell surface of a synapse, creating an inhibitory force at the synapse.
What is extremely odd is that early in development, the glycine receptor is NOT inhibitory, rather it is excitatory (or as the scientists say “depolarizing”) which means it generates action potentials). What is not known is why and when the glycine receptor becomes inhibitory. Perhaps it needs to be an exciter to infiltrate the NMDA gang of thugs, and only changes its colors when NMDA has become dependent on its presence.
These matters are being studied, but the switcheroo points out the extreme need for more funding to understand even the most basic of issues in pain transmission and inhibition. Glycine is perhaps even more important in brain inhibition than GABA, which operates at the cord level as the primo inhibitor. As you already know from prior articles, the glia which surround injured neurons release Nerve Growth Factor (NGF) which causes BDNF (brain derived neurotrophic factor) to activate, which not only redirects the gene protein factories to make pain exciters but ALSO blocks the action of GABA. Such a person can be said to be in torture. It is all positive feedback on the pain end. The normal situation is of course to have BOTH positive and negative feedback on pain. The brain needs to be able to enhance and suppress pain. Its condition in Central Pain allows only excitation. One can be distracted, but the pain cannot be reduced unless BDNF can be shut off.
See J. Kirsch from Heidelberg in Cell Tissue Res. 2006 Jun 29
You will recall from a prior article that NMDA, which is stimulated by glutamate must coact with glycine, a linkup which is still unexplained. There is also an important nitrosylation site on the NMDA recepotr, where Nitric Oxide (NO) can combine to whip up activity in the NMDA receptor (NMDAR).
Central pain patients are getting some outside help by virtue of NMDAR research, because excessive excitation by glutamate is thought to be associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. These are respectable diseases, considered worthy of serious research funding. Even ex-Presidents can get Alzheimer’s and what person does not fear Alzheimer’s a little. No one fears pain, except those who have it.
As dogs under the table, so to speak, and with no one fearing that they might someday acquire a pain state,(although one in five do) those with chronic pain must pick up the research crumbs which fall to the floor, and try to sustain our research with that. Fortunately, those few who work in our area are every bit as smart as researchers elsewhere, and it is positively amazing how well they are doing with nothing to fund them. Let the first drug company patent an effective ORAL N channel blocker, and you are going to see drug companies scurrying to try to develop N type blockers of their own. Drug companies are essentially German, so look for that country to attract the best.
As yet, the surveys do not show that any of the above conditions are more common in Central Pain; however, we have many reports of working memory loss in CP subjects. (Glutamate IS a big player in memory, not just pain).
Research is actually quite active in NMDAR blockers (antagonists) but how likely this is to lead directly to a treatment for Central Pain is not especially encouraging right now. However, we will get there eventually as more is learned about how the downstream pain chemicals interact, ie. downstream from NMDA and glycine.
NMDA is of course an excitatory chemical of chronic pain so its link with glycine and the switchover of glycine to inhibitory is more than a little confusing. Attempts to simply target NMDA or its coagonist, glycine, have failed clinically. However, the new derivatives of memantine, the nitromemantines, which draw NO to the channel noncompetitively (ie. allow other processes to proceed at the channel) appear to allow channel function to occur in needed functions while avoiding the tendency for NO to harm nerves.
This may or may not result in something to help pain, although memantine is even now used for neuropathic pain in multiple sclerosis CP. If enough scientists can be employed, we will reach our goal of effective treatment. Right now, work on pain outside the U.S. predominates, and it will likely be the result of work outside the U.S. if these pathways of pain should become evident. When we buy the pills to stop CP, it will almost certainly be from a drug company outside the U.S. Even within U.S. schools, it still appears to be foreign students who have the strongest background in biological science and pain. See Chen and Lipton J Neurochem. 2006 Jun;97(6):1611-26.
In a recent interview with Lance Armstrong who cycles with the President occasionally, he said President Bush was someone he liked and respected, but with whom he disagreed on spending. He was referrring to the pathetically small amount of money spent on basic cancer research (less than one billion in the history of the U.S.) compared to the half trillion spent so far in Iraq, a nation of fifty million people (although some census estimates are considerably lower, say 26 million). If you do the math, that is a lot of money for each citizen of that country, and a debt has resulted that will take a very long time to repay.
The total spent on anti ICBM missile defense research to date is ten billion. It is hard to imagine that our security is better preserved by spending in Iraq than in making the skies safer, although reasonable minds differ on this point.
We still think trade and medical cures are as good for peace and cooperation with other nations as anything else. It seems unlikely that citizens of any nation would want conflict with the one country which could cure them of cancer, pain, etc. This is not really a political statement, but there are millions suffering in pain in the United States, and their desire for freedom from it is not being honored. Six billion dollars in equipment is being transferred to the Iraqi army every month. Maybe one month we could save one billion and give that to the NIH for pain research.
We need more molecular biologists and biochemists. We need to train more, fund more, and hire more. The United States is great at producing weapons, but they have fallen behind in many areas of biological research. In the end, we may wish we had chosen another route. Biological weapons may turn out to be more important than explosive ones. The best weapons may turn out to be the offer of a cure, since no one wants loved ones to suffer. Foes of the U.S. survive mainly by demonizing the U.S. but this painting of the U.S. as an enemy would surely be more difficult if we were a powerhouse of biological cures with whom others would want to trade. Germany has a clear edge over the U.S. in pharmaceuticals, and Germany, England, France, Sweden, and Canada seem to be ahead in pain research. This is odd since pain is the NUMBER ONE reason why patients see a doctor in the United States.
Considering that the budget for basic pain research at NIH is a measly six million, employing less than ten scientists, we could hardly expect anything else than being third rate. We are perhaps second rate, which shows how hard our people are working. Bethesda Maryland is an expensive area. If you work hard, get your PhD in molecular biology and go to work for the NIDCR pain group, you might expect a starting salary of forty thousand dollars, well below what you can make out of high school as a garbage man. You will also get health benefit collecting refuse, something which the fellows at NIH do NOT receive.
We must ask what our long term goals should be and devote resources accordingly. It is not all on the President. Citizens and voters must also make good health a priority, and reflect it in the political issues they raise. Good medicine has a way of seeming very much like religion, and no matter what the faith, it would be hard to feel hatred for any nation which is delivering relief from suffering. Americans had better love foreigners, they are driving our technology in every area that does not require a security clearance. We just hope our rock and roll is good enough to make the world shop here, while we go overseas for such things as medicine and health care.