The Europeans are doing important work in ferreting out the little devils which make the pain system work, even when it is broken. If it is broken, DO fix it.
The chemical articles are dreaded by laypersons, but important for researchers, and we have something new to think about.
Chemical pathways in pain can be thought of as both core pathways and related pathways. Although this helps us to remember things, it is becoming harder to be sure what the core steps in pain are. The related pathways may be very important in nerve injury pain. The kinases, the chemicals which attach high energy phosphates which act as a battery, are equal in importance to the primary neurotransmitters.
A recent article here suggested that it is helpful to think of central pain as having TWO arms, failure of injured neurons to perform pain inhibition, and the overproduction of excitatory pain chemicals under the influence of growth factors. This article refers to the second aspect, namely the overproduction of pain exciter chemicals by the chromosomes in neurons and surrounding cells. This aspect of nerve injury pain is known as “exciter toxicity”.
Proteins are not only chemicals, they are structures. They are built, step by step, fitting together the pieces in a fashion so complex, that it makes us wonder how nature ever accomplished it. Proteins have almost impossibly intricate shapes. This individual nuances of shape are determined by genetics and by the electric forces of the atoms and molecules which make up the protein. It is the result of so-called “bonding angles” inherent in the attraction and repulsion of atoms and atomic particles.
In order to make a protein, it is necessary for shapes to “fold” as the protein goes through one configuration to another until these finished product is reached. Acids change the shape of configurations and end products and definitely affect function.
Shape is tremendously important. For example, “sweetness” is a shape, not a chemical composition. If a chemical has a certain shape, it will taste sweet, no matter whether it is a sugar or not. It takes a computer even to draw the shape of a protein. Think of a bolt of ribbon piled in a curled heap, which then comes alive as a moving creature, and you get the idea. It is useful to think of a protein as similar to the toys which can be turned from robot to airplane with manipulation of shapes. Proteins may stay in one configuration for less than a thousandth of a second, but the stepwise configurations are all necessary to reach the final mature protein. If too much acid is present at any stage of construction, things can go seriously wrong.
What we call “Mad Cow disease” is an example of something similar. Central pain is a type of “mad channel disease”, the channels of relevance being the VR-1 calcium channel and the Nav 1.3 codium channel. Channels may not transport ions, channels may open too wide, channels may stay open or may never open. Channel proteins are among the most amazing of structures, and are made up of organized arrays of simpler proteins manufactured by the genes of a neuron.
It is helpful to think of acid as changing the shape of the component parts. A structural protein is not just a bullding block, it is a micromachine of sorts. The proteins in ion channels move, change shape, form structures, open and close, move ions such as sodium or calcium across the cell membrane, and act almost like a living thing.
The failure of the inhibition arm includes the failure of injured neurons to manufacture the protein chloride carrier, KCC2,which is necessary to permit the chloride step in inhibitory signals. The second wing has to do with genetics. As far as pain is concerned, genetics means the unleashing of gene protein factories to manufacture pain chemicals. Almost all scientists agree that this occurs when nerve growth and repair factors are produced in response to nerve injury, and affect neurons which are so badly damaged that they cannot respond properly to the growth factors, causing such things as fetal ion channels and pain kinases, which activate pain chemicals, to be overproduced, leading to hypersensitization of the pain nerves.
While we do not expect readers to grasp the chemical pathways, it is hoped that they will be able to speak of the VR-1 channel which causes dysesthetic burning, the function of kinases in powering pain chemicals, and can recognize the names of the three pain pathways occuring at the nerve synapse (connection point), which includes:
3) Neurokinin 1 (NK-1)
In the past it was common to say that NMDA mediates chronic pain, AMPA mediates fast pain, and Neurokinin does SOMETHING. It may be helpful to you to refer to the Neurokinin pathway as the PnP pathway, which stands for Substance P, Neurokinin-1, and Protein Kinase C. This naming for the neurokinin pathway mentions the big players in a sequence of chemical reactions leading to the production of pain kinases, which activate pain, including the central pains.
They might also remember that the sequences of pain exciter chemicals which lead to central pain are known as the MAP kinase and ERK cascade, that pain exciters are manufactured by genes under the influence of nerve growth factors, and that enough pain chemical is around in CP to make the cells in the cord fire continually without any stimulation. They might also remember that this signal goes to the thalamus in the center of the brain, and from there to the back of the central gyrus (locates pain), to the parietal cortex (identifies the pain) and to the insular cortex (painfulness of pain–see Francis Crick article at this site). All of these concepts are covered elswhere at this site and can be located using SEARCH. They may also recall that the emotional feeling of pain routes to the frontal cortex and to the anterior cingulum.
Very early on, following the proposition raised in Oct 02 IASP Clin Updates, painonline suggested that the pH changes associated with perineural acidosis would affect structure. Proteins are very complex molecules and their shape “folds” according to changes in pH, and also according to any insertions or deletions in their formative components. The shape or configuration of proteins is essential to performing their function. They must often fit in place and changes in structure prevent this.
Organic proteins are very sensitive to pH in their shape and function. The study of pain chemistry is basically the study of the effects of acids on pain neurons. When you see the words prostagladin E, arachadonic acid, fatty acids, fatty acid hydrolase, interleukin, leukotriene, cytokine, etc. you are seeing the names of chemicals which make the nerve membrane (aka plasma membrane) more acidic.
Monastyrskaya et al in J Biol Chem. 2004 Dec 8, have shown that neurokinin 1 is involved in pain transmission and smooth muscle operation (in gut/bladder). Given the presence of abnormalities of both of these in various CP subjects (light touch pain in skin, pain sensation of overfulness in the gut/bladder), it is interesting to learn that neurokinin 1 occupies a specific place in the cell membrane, and that structural blockade of that level ends pain associated with neurokinin activity. The idea that neurokinin has a specific place in the membrane, in the so called lipid raft, is new and once again points to three dimensional location as important in pain. Again, rendering the lipid raft locations inoperative, ends pain.
Also noteworthy is the study by Bierhaus in the Dec 04 J Clin Inv, wherein he showed that RAGE (a receptor associated with advanced glycation products) receptors maintain the genetic production of a certain neurotrophic factor (NF KappaB) and the interleukins. When you see Neurotrophic factor, you should think of a chemical which can turn on genetic protein factories to stimulate production of pain related chemicals. When you see When you see interleukin you should think of pain chemicals associated with perineural acidosis and the action of opioids. Bierhaus has pinned the flag on RAGE chemicals as a player in the cascade of pain chemicals. Blocking rage blocks peripheral pain.
Thus, the march to understanding of the bit players in pain chemistry, which gain starring roles in central pain, continues. May we thank the researchers and wish them godspeed. We have had a good long wait.