Insane in the Membrane

All membranes are different. None of them is indestructible.


Because of questions which have been received, it seemed appropriate to review a little about membranes. In the world that can be seen with the naked eye, membranes are not particularly important. We do not build buildings of them. We don’t really think of our skin as a membrane. The outer layers of skin are dead, just as is the hair. So what is a membrane and what does it have to do with pain? At the microscopic level however, membranes are a big deal. Actually, not the membrane itself, which can be formed simply by putting certain fats in water. What is important is the structures embedded in the membrane, which have been manufactured in the cell, including the channels.

First, a gene is a part of a chromosome. Fractions of the genes, known as exons, are coded into messenger RNA to make components or amino acid sequences. Amino acid sequences in smaller numbers are known as peptides. Assemblies larger than 200 amino acids are known as proteins. Proteins may be composed of a number of similar building blocks, such as in the case of Calcium channels, which primarily are made of the alpha 1 subunit, but have auxilliary groups as well.

Proteins can dissolve, form, move, contract, and do a number of things which makes them a type of micromachine. Wrapped in a helix or in a cylindrical shape, the proteins can form channels, which sensitively control the passage of calcium, sodium, potassium, or chloride ions which control the electromotive forces in a cell. When charged particles are compartmentalized in opposite groups, we have a kind of battery, capable of generating a current. The aggregate frequency of current spikes (action potentials) in a pain nerve determines how much pain signal is going into the system. (A nerve is a collection of MANY neurons, or individual cells).

There are several concepts of the cell and membranes which are important. Within nerve cells, or neurons, chemicals known as neurotransmitters help relay and receive signals. It is inefficient for the body to completely remanufacture anew neurotransmitters at the gaps between nerves, so the neurotransmitter tends to be released, act on a receptor, and then be taken up again to be reabsorbed by the nerve ending which released it. This step of release and reabsorption may also help in regulation, as a way of achieving an “off” as well as the “on”. As it is reabsorbed, it is placed into a little “bubble”, or vesicle. These little bubbles then fuse, and remain ready for release once again. A neurotransmitter is like the ball in a pinball machine. The receptors are hit, and then may be hit again. In some states the “ball”, or neurotransmitter form a chemical bond to the receptor permanently, making that receptor inactive and useless. An example of this is Parkinson’s Disease. Among other causes, such as loss of DII receptors from age, use of certain amphetamines (crystal meth) fixates the dopamine II receptor, making it useless forever.

There are perhaps 25-50 chemicals which cause vesicles to form, fuse, and then release the neurotransmitter again. Calcium, recently reviewed here, acts as a mediator and facilitator of the chemicals which govern vesicle fusion and function. Thus, even though it is the sodium channel which actually fires the action potential or nerve spike, it would never happen if calcium channels were not operating. The signal generated in a neuron would never make it across a synapse, or nerve junction. The vesicular membrane is composed of proteins, manufactured by genes in the nucleus of the neuron.

The types of chemical reactions operating in a neuron are often regulated by chemicals manufactured by cells surrounding the neuron, the glial cells. Things like growth factors, repair factors, and factors related to the kinases, or energy suppliers, come from the glial cells. In nerve injury, these growth factors do their job too well, causing too much gene expression. It is not known what drives this glial franticness, but it may be the local acidity which builds up from release of certain materials from injured nerves, or it may be in response to superoxides which are released. The genes making pain exciters get carried away and stay carried away, continually driven to repair the neuron, which never quite returns to normal.

Next we will speak of the membrane of the neuron. Nerves are under feedback control from the brain. To achieve greater speed of transmission, the neurons move nearer and further away from firing all the time. If need arises for a quick outburst, many of the neurons are so ready to fire that they do so instantly. Because those near firing drift over the edge and fire automatically from time to time, (not unlike the way molecules at the surface of water occasionally escape, causing evaporation) we observe a certain level of activity constantly in the nerves. ALL neurons are firing at some rate ALL the time. This causes tremendous noise in the brain, which must spend most of its energy inhibiting these signals.

The efficiency, speed of firing, and impact are largely a function of how channels operate at the membrane. Remember, the channels are manufactured by gene expression and migrate to the cell membrane where they embed. The number and type of channels govern how a cell operates. If you altered the channels, the membrane would acquire new characteristics. Instead of acting like a pain neuron, it might act like the sensory neurons that control balance, or something else. While the manufacture is going on inside the cell, the real action is at the interface of the membrane, which is where the channels are.

In nerve injury, the genes begin to manufacture a FETAL sodium channel, the Nav1.3. We won’t go into how these channels are numbered, but it has to do with their behavior. The normal human has NO Nav1.3 channels operating, but rather uses the Nav1.8 channel for chronic pain generation. The membrane becomes peppered with Nav1.3. Ordinarily, the cell would move chloride to the membrane to temper excess activity because negative ions are inhibitory at the membrane. While injured nerves make TOO MUCH of the channel proteins, they make too little of other proteins, such as the KCC2 protein, which moves chloride to the membrane. This means that inhibition does not occur. The inhibitory switch has ceased functioning, and ANY SIGNAL FROM THE NEURON WILL THEN BE EXCITATORY.

This condition is known as hypersensitivity or hyperalgesia, and the clinical condition it causes is known as central pain. For various reasons, we know that the abnormalitiies travel to the brain in CP and are not limited to the neurons out in the body. Although it can do other things too, the main kinase or energy supplier for pain exciters is protein kinase C. This is the chronic pain kinase. The main pain neurotransmitters are two acidic amino acids, glutamate (cord) and aspartate (brain). The inhibitory neurotransmitters include GABA (a slight alteration of glutamate) and glycine (an amino acid).

Other pain suppressing tracts use the familiar neurotransmitters acetyl choline or serotonin. It is not really the neurotransmitter which matters, it is the receptor. A receptor in an inhbitory brain tract may be ACTIVATED by aspartate, but CAUSE pain inhibition. Fortunately, the transmission of a signal requires vesicles of neurotransmitters to form at the nerve ending, the presynaptic area. Calcium channels control the formation of the vesicles and a unique one operates in pain nerves. This unique channel is the CaV2.2. The previous articles at this site on voltage gated (open and close as voltage changes) calcium channels explain how researchers hope to exploit the CaV2.2 channel and block them with conotoxins or similar drugs. This is possible currently, but the medicine must be given into the spinal fluid. What is needed is an oral drug which accomplishes the same thing, blockage of the CaV2.2.

There are other types of membranes as well, such as in the kidney. Compact tortuous loops of blood vessel extrude small chemicals into the urine. Next, those chemicals which need to be retained are reabsorbed by active transport, which means energy is consumed to draw the chemicals back into the blood before it leaves the kidney. This operation is NOT the same thing as the membrane of the neuron, which relies on tiny pores. Relatively large chemicals, such as sugar, can be reaborbed at the kidney.

In pain nerves, there is a receptor which is excitatory, known as the TRPV-1, formerly the VR-1. This is the receptor for capsaicin, and use of capsaicin in rats helps scientists understand central pain. The CaV2.2 is the calcium channel which causes the TRPV-1 to operate. Researchers speak of blocking CaV2.2, or also of blocking the entire TRPV-1 site. This latter step can be done with resiniferatoxin (RTX). RTX destroys the TRPV-1 by destroying the outer membrane and the membrane of the mitochondrion in the cell, as well.

RTX has yet to be applied to the dorsal root ganglion, but it is used to destroy TRPV-1 in the bladder to cure neuropathic bladder pain. RTX acts instantaneously, melting the membrane chemically, as it were. It does not cause pain to the user, who apparently does not have time to show pain before the membrane is destroyed. RTX is very potent. One researcher dipped his finger in a solution of it and tasted, but his mouth went numb for a month or two. All of this suggests we are on the right track. We just have to keep going.

Thus, we see that membranes are important. When they stop functioning, terrible things can happen. We hope to see drug companies explain precisely how and where their medications are acting, so that we can understand which ones really represent soemthing different for us to try. You may wish to review the articles on calcium channels to better understand what is currently known. Yes, those with CP are insane, “insane in the membrane”.