Neuroinflammation in Central Pain

The scientific world is getting ahead of the American Doctor’s office on pain theory. Pain chemistry is not a field in doubt, it is a field ignored. It is politically incorrect to legitimize pain patients. People who ought to be out pursuing the bad guys in swamp buggies in Florida find it more convenient to sit behind desks and arrest and imprison pain patients and their doctors.


Is there anyone left in America who doubts that those who consume alcohol are more wasted and constitute a greater public danger than those who consume opiates for pain? Until the government understands the panic of the pain patient who fears running out of pain pills and tends to stock up on them, we will continue to act silly and unenlightened in dealing with pain patients. The “holier than thou” attitude has to be replaced by the realization that ANYONE with a severe pain state will worry about having enough meds. The answer is to cure pain, not to expand the bureaucracy.

Even remote countries with relatively small amounts of resources are turning out very respectable papers with respect to pain chemistry. Too bad the clinicians are not reading the journals. They would take CP patients more seriously.

As it stands now, when pain is ended the patents will most likely be held by some country other than the United States, which still punishes or ignores pain patients. It is tempting to think the draconian enforcement of opiate control laws in the U.S. has led to a reluctance to touch pain at any level. Pain treatment is the “beltway boogeyman”.

It is time to cease the hysteria, as if pain patients were zombies threatening to engulf the nation in a crazed hunt for oxycontin, and start curing pain. The idea is, no one really has pain, and so no one really has the right to seek treatment. We are a nation ruled by law, but it is time for a little common sense as well. “The Law is an ass.”–Charles Dickens.

We have already printed a large number of articles dealing with inflammation and its link to pain in the central nervous system. Some of these articles are puzzling to some readers, so we adopt a new term to make clear that when we speak of inflammation, we are talking about a unique form, which differs from inflammation elsewhere in the body.

However, because “inflammation” is a common term in the body, we wish to indicate that we are interested in the specific way the nervous sytem inflames. It seems best to distinguish this niche by terming it “neuroinflammation”. Finding a way to stop repeatedly defining what we mean when we use the term “inflammation” frees us from repeating how ordinary inflammation is different from changes in the nervous system. And so from here on, when you see the word inflammation at this site, you should read it to mean “neuroinflammation”, unless otherwise indicated. The neuroinflammation results from abnormal gene expression, which makes abnormal amounts of kinases which activate pain proteins, causing nerve injury pain.

A great deal of research has been generated recently on cell adhesion molecules. (see the prior article here on sialic acid). Now Wu et al publishing in Life Sci. 2006 Feb 4 have reported on a possible model for how this works in nerve injury pain. The model is a chemical, lipoteichoic acid, (LTA) which is an integral component of the cell wall of gram positive bacteria, such as staphylococcus.

Wu discovered that LTA interacts with a substance identified as CD14 to induce Neurotrophic Factor-kappaB activation, which is in turn involved in transcriptional regulation of adhesion molecules, enzymes and cytokines. You recall that protein production involves transcription from the DNA of genes into amino acids which via messenger RNA are carried out into the cytoplasm of the cell to be TRANSLATED into proteins.

It turns out that LTA activates tyrosine kinase, phospholipase C, and phosphatidylinositol-specific phospholipase C, which you will hopefully recall as pain related chemicals. Phospholipase C, currently under intense study by Tony Yaksh at UCSD, in turn induces extracellular signal-related kinase (ERK) activation, which leads to prostaglandin E2 release and cyclo-oxygenase synthesis.

Now what does this tell us. It tells us that regulation of the genes which make cell adhesion molecules are important not only in cancer, which is their traditional area of study, but also in pain. It would appear that Tumor Necrosis Factor (TNF), which tends to clean up dead and dying cells is blocked by certain cellular adhesion molecules. It may be possible that injured pain generating neurons avoid cell death by the chemical processes which cause outpouring of LTA-like substances, yet to be identified, which permit other growth factors to attempt to maintain damaged neurons rather than allowing TNF to come in and kill them. TNF is a focus in cancer research because it seems to signal both cell survival and cell death (apoptosis). In conjunction with TNF, NF-kappaB seems to signal cell survival while c-Jun N-terminal kinase (JNK) signals cell death.

LTA also increases tyrosine kinase and we have shown that tyrosine kinase A (TrkA) and B are intimately involved in pain neurons. The presence of TrkA is a marker that a given neuron is a pain neurson. AIDS researchers are looking for the precise sequence of the virus which is shared by all strains–this sequence is called the “Holy Grail” of AIDS research. An antibody to it might end AIDS. Similarly, it might be possible to find the amino acid sequence which is unique to tyrosine kinase A and kill these cells, or at least reduce their number. We all need a little pain, but those with CP could do with a whole lot less and still protect our joints from abnormal postures and our skin from cooktop surfaces.

Gene regulation is an interesting area and seems destined not only to be behind cancer but also responsible for nerve injury pain. We need more research into the molecules which cells make to accomplish binding. Exactly why these adhesion molecules would cause phospholipase C production is still being investigated, but there is little doubt that PLC is important or even central to the maintenance of Central Pain and has links to ERK which of course has links to MAPK and all the pain exciter kinases (see prior articles on MAPK and pERK).

This work was done in Taipan. Knowledge of pain chemistry has penetrated virtually the entire scientific world, with the exception of the American doctor’s office which has still not come to grips with this new knowledge and prefers to ignore or deny the reality of nerve injury pain. To do so requires deliberate blindness to the well established literature on the reality of nerve injury pain. Most of you who have been following or attempting to at least skim the articles here are aware that nerve injury pain involves abnormal gene regulation such that genes which produce the proteins that become pain exciters are upregulated and possibly producing at maximal levels, having lost ordinary controls. The end result is acids, fatty acids, which hypersensitize pain neurons and result in nerve injury pain.

LTA, our model for understanding, acts at the transcription level to induce neurotrophic factor activity. (see article at this site on neurotrophic factor, using SEARCH). The nerve growth factors result in an outpouring of pain exciters. The primary growth factor behind this is Brain Derived Neurotrophic Factor which suppresses GABA(A) so pain inhibition cannot take place, resulting in hypersensitization. However BDNF has helpers in the other growth factors including NF and tumor necrosis factor (TNF).

Wu states, “Although there are many aspects to neuroinflammation, the pathways involving the cyclooxygenase (COX)-2 and subsequent generation of prostaglandin clearly play a role.” You should think of acids at the nerve synapses when you read of cyclooxygenase 2 and cytokines.

Our model, LTA, provides insight into how a cell adhesion modulator might preserve damaged cells which inevitably lead to outpouring of neurotrophic factors, which in turn upregulate production of pain exciters. We have already printed a large number of articles dealing with inflammation and its link to pain in the central nervous system. Some of these articles are puzzling to some readers, so we adopt the new term, “neuroinflammation” to make clear that when we speak of inflammation, we are talking about a unique form, which differs from inflammation elsewhere in the body. Neuroinflammation shares the acid producing in genes, but it differs in the large amount of neurotrophic factors and often lacks the chemicals which attract large numbers of white cells to the area, although as described in a prior article certain inflammatory cells, such as mast cells ARE attracted.

It turns out that LTA activates tyrosine kinase, phospholipase C, and phosphatidylinositol-specific phospholipase C, which you will hopefully recall as pain related chemicals. Phospholipase C, currently under intense study by Tony Yaksh at UCSD in turn induces extracellular signal-related kinase (ERK) activation, which leads to prostaglandin E2 release and cyclo-oxygenase synthesis.

Now what does this tell us. It tells us that regulation of the genes which make cell adhesion moleculars are important not only in cancer, which is their traditional area of study, but also in pain. It would appear that Tumor necrosis factor, which tends to clean up dead and dying cells is blocked by certain cellular adhesion molecules. It may be possible that injured pain generating neurons avoid cell death by the chemical processes which cause outpouring of LTA-like substances, yet to be identified, which permit other growth factors to attempt to maintain damaged neurons rather than allowing TNF to come in and kill them. LTA also increases tyrosine kinase and we have shown that tyrosine kinase A and B are intimately involved in pain pathways.

Gene regulation is an interesting area and seems destined not only to be behind cancer but also responsible for nerve injury pain. Strangely, lack of control of the respective membrane binding proteins seem to underlie the lack of chemical regulation in both conditions. Cells which probably ought to be killed are not destroyed, with the result that the nerve repair factors which follow by pouring out nerve growth factors, many of which send pain exciters wild, gum up the works. We need more research into the molecules which cells make to accomplish binding. Exactly why these adhesion molecules would cause phospholipase C production is still being investigated, but there is little doubt that PLC is important or even central to the maintenance of Central Pain and has links to ERK which of course has links to MAPK and all the pain exciter kinases (see prior articles on MAPK and pERK).

This work was done in Taipan. Knowledge of pain chemistry has penetrated virtually the entire scientific world, with the exception of the American doctor’s office, which has still not come to grips with this new knowledge and prefers to ignore or deny the reality of nerve injury pain. To do so requires deliberate blindness to the now well established literature on the reality of nerve injury pain. How many U.S. physicians could give a credible description of how nerve injury pain feels and how that differs from normal pain. The U.S. Doctors may well be the last group on earth to understand that old ideas about pain are obsolete and that one must spend the time to update.

Those who put on the white coats must now devote the necessary study to understand neuroinflammation in order to properly hear the neuropathic pain patient. Doctors may not be the greatest chemists in the world, but they do understand that acids burn. If they come to realize that activated fatty acids saturate the synapses of an injured nerve, that will be a beginning to understanding the burning which characterizes central pain. It is quite possible that the PhD’s will have a cure for Central Pain before the doctors even admit it exists. Pain politics is currently strongly anti-patient. This is a tragedy.