Many readers seek more information on the mechanisms of pain. Get a start by understanding the generator potential, the pilot light of pain. Learn why Central Pain does not need a pilot light.
Whether it be the starter motor in a car which gets the big motor turning, or the pilot light on the stove, small things can initiate big things.
Nature is no different. Everything in the pain system is frequency modulated, which is to say the degree of pain is NOT determined by the power in an individual nerve firing, it is in the FREQUENCY of the firings. Frequency is what means something to the brain. Every neuron sends random firings up its axon to the next neuron, more or less continually. The brain ignores this noise.
An individual nerve firing is known as an action potential. Just as electons would like to flow if the positive and negative ends of a battery are connected, ions would like to flow across the membrane of a neuron. The flow is large through controlled gateways, known as ion channels. Ion channels have a surprisingly complex shape and the array of channels is also complex. The shape may resemble a tubular bell, twisted and contorted into moderately similar loops, which go back and forth across the membrane.
An ion is simply an atom which has lost or gained an electron. Negative ions are held inside the cell by certain carrier proteins. KCC2 is one of the proteins holding chloride (Cl-). Coull showed injured nerves cannot manufacture chloride, preventing inhibitory action by neurons.
Ion channels move sodium inward, and at least ten are known for sodium. A peculiar ion channel, Nav1.3 is known only in the fetus. Nav1.3 is also the ion channel responsible for the pain of nerve injury. Why should a fetal ion channel reappear in an adult. Apparentl various growth factors attempting repair of an injured cell kick Nav1.3 into production by the genes of the neuron cell.
Sodium (Na+), which is relatively increased outside the cell by a chemical pump which excludes it during resting intervals, flows into the cell across the membrane during a firing, or action potential. Other ions flow outward. The more ions which have been displaced across the membrane, the greater the voltage difference between the inside and outside of the neuron.
The resting potential, or difference between the outside and inside of the neuron membrane, is in the range of -60 to -90 millivolts. During firing this difference disappears very briefly. A pain nerve can fire with as high as about 50 action potentials per second. When the potential difference is great, we call it “hyperpolarized”, or less ready to fire. More compensatory ion flow must occur for an action potential to occur in a hyperpolarized state.
A “hypopolarized” membrane is more ready to fire. Less of a voltge difference must be overcome before ions can begin to flow across the membrane. When ion flow is accomplished at the membrane, we call it “depolarization”. Depolarization kicks off a self generating pulse of energy which travels along the neuron like dominoes falling in sequence. The propagation of the action potential is how neurons send a signal, or fire.
Positive ions are excitatory. Negative ions are inhibitory. Some ion channels open because they are exposed to a voltage change, the so called voltage gated channels. Other channels are opened by the facilitating action of some molecule or “ligand” which energizes the channel. There are even channels which open due kinetic energy, which comes mainly from body heat.
Biologists speak of a potential, meaning the potential to cause ions to flow, while a physicist uses another term for the same thing, namely, voltage difference. Normally when one hears the word, “potential” a discussion of ION flow can be expected, and when one hears “voltage” one can expect a discussion of electron flow. Your toaster runs on the flow of electrons, while your body runs on the flow of ions.
Normally, when some adequate stimulus appears at the skin, a small (-20 millivolt) “generator” potential is set off. Whether a generator potential occurs has to do not only with the strength of the stimulus but also the nature of the receptor. Various types of receptors occur at the ends of axons, and some axons do not have a true ending at all. Small, unmyelinated nerves are known as C fibers. They are the ones which normally lack a specialized ending. C fibers contain the VR1 receptor, which is the one that is thought to evoke Central Pain. It is also activated by capsaicin, and is sometimes called the capsaicin but still the VR1 or TPRV-1 receptor.
The generator potential at the nerve ending kickes off the bigger action potential, or gets it started. Normally, a nerve fiber or axon cannot generate an action potential. The action potential must start at the nerve ending. However, in CP, the ENTIRE axon, or nerve fiber has the capacity to generate its own action potential. This condition is quite abnormal. Tasker showed that radiostimulation at the neck in CP patients reduplicates their pain, while the normal person feels nothing at all. So one might conclude that the axon has become so hyperexcitable that axon may generate its own firing along its entire length and is no longer dependant on a generator potential.
If a car gets sufficienty hot, it can sometimes keep running after the key is turned off. This is known as “dieseling”. A nerve fiber or axon which is sufficiently hyperexcitable, can fire without apparent meaning. This condition in humans is known as neuropathic pain.
Now you know how things work. There is still a lot to be learned. Why are there so many channels for sodium and other ions. Why won’t just one do? The voltage spike, or action potential takes place over time, and the precise timing of ion flow is still being worked out. Nature’s subtlety is amazing. There is still a great deal to learn. One of theese steps will provide a chance to block neuropathic pain. It is important to remember that action potential propagation in normals, which typically uses the Nav1.8 channel for pain, is different from the ion behavior in CP, which uses the Nav1.3 channel. Nav 1.8 typically does NOT participate in Central Pain.