Thanks once again to McGivern and McDonough for providing the materials on which this series is based. The culprits in central pain, the calcium ion channels (complicated pores) in the membrane of the neuron, are further described here. For simplicity’s sake, it may help to think of a channel as a very long lens shaped tubule, containing angles and many series of shutters, in which the leaves of the shutters open and close in sequence to “squeeze” calcium through the neuronal membrane, with other structures able to slow or increase the calcium flow by keeping the leaves of the shutters in wider or narrower position.
VOLTAGE GATED CALCIUM CHANNELS
Although these articles are intended to be self contained, some may wish to read further and references to other topics at this site are given for those interested.
The role of protein kinase C in upregulating the genetic production of the alpha 1 subunit is described. To a lesser extent, the impact of failed G protein function in pain inhibition is mentioned (See below at the *).
A magnet has a positive and negative pole. Every Scout who got the electricity merit badge knows that if you wind a copper wire arounda magnet and spin it, current flows in the wire which will light a small bulb. Movement of charged particles generates a current. When a charged particle, such as an electron or ion, undergoes movement, a current is generated. In a neuron, the current comes from ion movement through channels which cross the neuronal membrane. In the nervous system, this is used to generate and propagate an action potential, or voltage spike. The outside of the cell is negative relative to the inside. This is true because the membrane has been readied, or “cocked” by polarizing the inside from the outside. The difference must be sufficient to “polarize” the membrane, but not so great that the oncoming action potential from further out on the nerve cannot make the action potential fire.
Thus, neuron firing may be inhibited by two methods, preventing polarization, and also by making the polarization so great that the train of action potentials marching along the membrane is stopped. The voltage difference is so great, that it cannot be affected by the oncoming action potential which lacks the punch. In reality, these mechanisms may work either at the membrane itself, or more commonly in the local area of the channels.
The frequency of the voltage spikes determines the strength of the pain signal from a neuron, and the aggregate frequencies from many neurons making up a “nerve” is read by the thalamus as pain. To achieve a propagating voltage spike, or action potential, many things must happen. The following will be an oversimplification:
1)First the ouside of the cell must become negative with respect to the inside. This happens when ions are transported across the membrane selectively, either through passive flow or against a gradient, consuming energy. Once the difference in electrical potential is set up, the cell is polarized and ready to fire.
2) Normally, a nerve ending is stimulated, causing a generator potential, which is relatively weak, about 20 miliivolts. This kicks the neuron into gear and it then generates action potentials which move up the nerve. IN CENTRAL PAIN, ANY PART OF THE MEMBRANE CAN PRODUCE A GENERATOR POTENTIAL, NOT JUST THE NERVE ENDING. This is a radical change from normal.
An individual neuron can fire maximally at about fifty times per second and the combined nerves made of neuron cells can fire maximally at around one thousand spikes per second. The small C fibers which are most involved in CP are relatively slow and tend to set up geenral conditions of pain hypersensitivity rather than fire rapid pain volleys. This is not true of the lightning pains of the posterior cord running in the large, rapid alpha fibers recruited at cord level by the C fibers coming up from the peripherae to the cord. Lancinating pains are very rapid and intense, sometimes causing unbearable pain, but only INTERMITTENTLY. The periodicity of lightning pains varies from something like once a week, to many times per minute. In the majority of cases, the severe jolts may only happen several times in a row for for a period of minutes. The CP subject hates them but knows they will stop. They are therefore considered to be much less devastating than the constant burn from the C fibers, which never stops in many individuals.
Electrodes in the thalamus record nerve injury firing as dense clusters of repeating discharges known as “bursts”. If your thalamus is firing off bursts continually, you have central pain, the frequency determining severity. Actually, the thalamus is more complicated than this and responds to bursts by generating waves of current to the cerebral cortex at various frequencies, known as thalamic oscillations. Some feel the signal oscillation of CP occurs at 0,2-0,5 Hz, which is rather slow as brain waves go. Sometimes imposing a blocking current at 25 Hz or above may diminish the CP, but the risks of deep brain surgery are presently considered too great to perform. For unknown reasons, stimulationo of the motor cortex in the brain also may relieve central pain, possibly by interrupting the thalamo-cortical or cortico-cortical signals necessary for pain perception. This requires opening of the skull and there are reports of phantom limbs being created, so great caution prevails at the present with MC stimulation.
The oscillations in the frontal cortex register the significance and impact of the pain. Signal in the postcentral gyrus or somatosensory cortex indicates the location of the pain. Signal in the insular cortex from the oscillations and resulting cortico-cortico circuits subserves the painfulness of the pain.
As above indicated, anything which increases the voltage difference between outside and inside of the neuron, causes hyperpolarization, ie. a more powerful battery, which can fire and reload faster. Again, frequency is the key. Actin potentials are all or nothing at all. Either they fire or they do not. Anything which weakens the potential difference wears out the battery and the neuron cannot fira as rapidly (inhibition), if at all. The rate of reloading is a function of several factors, including the number of calcium channels, which is controlled by the rate at which genes in the neuron manufacture the alpha 1 subunit, which is the major building block of calcium channels.
A second messenger is something which completes what was initiated by something else. That something else is usually a neurotransmitter. Neurotransmitters have gotten all the publicity in the past, but now we know they can be nonspecific and it is the nature of the receptor which determines what the resulting action is. Calcium acts as a helper/regulator, or “second messenger”, but also as a modulator to the processes primary to an action potential, which involve sodium, chloride, and potassium ion flux.
Calcium flows through different types of channels, all of which seem to be made of a variety of molecules known as alpha 1 subunits, and which have additional parts to help in the operation, such as the alpha 2 delta subunit. Some of these parts cross the membrane and some do not. It is rather complicated but happens at dazzling speed, with calcium able to flow through the channels in milliseconds. Although it happens at the molecular level, there is nothing imaginary about this. It is a real event with real pain consequences, no matter what “theories” about your pain may be advanced by the uneducated.
Infinitesimally small amounts of toxin which block calcium activity are fatal. Similarly, if the calcium channels open or close inappropriately, the pain signal loses inhibition or alternatively, goes wild. If a snake manufactures calcium modifiers in its genes and injects it, things happen. If you manufacture your own calcium channel factors, things also happen. The reason the public doesn’t get this is that the snake or spider is missing. The effects are still there, for you alone to experience.
This condition of overproduction of exciter channels and defect in pain inhibition is known as central pain, the most severe pain state known to man. It is unimaginable in its features, because normality requires normal chemical pathways. The unique mixtures of pain sensations combine to cause complex perceptions which are indescribable. Because pain is normally the most singular of sensations, and because pains do not normally mix in the thalamus, it is hard for the general public to grasp that what is felt is more painful than normal pain. This is true because of the large amount of the body which is in pain, possibly the entire skin surface, and also because the pain never ends. Hence, Dr. Riddoch’s famous description of central pain as a “pain beyond pain”.
CP comes in gradations, and nearly always includes a feeling of acid under the skin (where nerve endings are), or a burn, which can be anything from sunburn level to a state so sensitized that clothing cannot be tolerated for more than brief periods and prolonged light touch of any kind is unbearable, including the touch of sheets.
Central pain is “channel disease”. The genes making proteins from which channels are constructed have been upset by kinases and growth factors released in the nearby environment. It appears the nerve would like to repair itself, but the neurons cannot respond properly. Neither can the neurons inhibit themselves since the defective calcium channels mishandle the calcium that normally faciltates inhbition of pain caused by potassium channel function. This inhibitory function reflects inadequate production of G protein which is necessary for the steps to be completed normally (see below).
Local voltage changes open some of the channels, while others may respond to G proteins (or for sodium channels, even the kinetic energy of heat). Channels are moving, shape shifting protein structures, often assembled out of multiple units which are prebuilt by the genes in our chromosomes. Structural proteins are properly termed micromachines, since they open close, and move materials along. In this article you will discover why we have discussed protein kinase C in prior articles and also, how G proteins can perpetuate aberrations in injured neurons for a very long time, long after any particular molecule of neurotransmitter has been consumed.
Farther up the line, the brain reads collective frequencies of action potentials to create sensation, in this case pain. Pain is a construct, or sensation which the brain creates, as a warning. The calcium ion channel in the neuronal membrane plays a major role in crafting a pain signal. Calcium 2+ is a charged ion which passes via various types of channels, to create a “calcium current”. In a grand oversimplification, central pain is caused by too much calcium ion associated current flowing through the calcium channels, and possibly with interference with potassium current as well, where the brain is concerned (see below). The hyperexcitability of neurons (nerve cells) in central pain is not questioned. Neither should the pain perceived be questioned, nor should it be attributed to some obscure, unassociated mechanism, especially a psychological mechanism. If the carburetor in a car is stuck open, the roaring of the engine you hear is NOT psychological.
As mentioned in the prior article, calcium channels are found in many types of cells. In the early studies, differences in the calcium ion currents through channels was sorted out according to:
1. How long a single channel remained open during an action potential firing
2. How much calcium could pass through a given channel (ie. Conductance)
3. How fast the channel was inactivated as the time duration of the action potential was lengthened
4. The voltage (potential) at which the channel was activated or opened, and the voltage at which it was inactivated or closed. The outside of the neuron is typically -90 millivolts compared to the inside of the membrane. As the action potential fires, this polarization disappears or the membrane is depolarized. The depolarization is the central firing mechanism of an action potential to be transmitted in