Pain echoes its way up to the brain, but when there is Central Pain, the signal is amplified at each “bounce” across a synapse. Each bounce represents acid production and action at the sodium channels to cause hypersensitivity. Other ion channels are involved also, but are not discussed here.
We will speak here only of the spontaneous burning dysesthesia. Evoked dysesthesia is a heightening of the spontaneous, caused by some stimulus such as light touch or temperature change. In some way it almost certainly follows the spontaneous dysesthesia. However, as Weir Mitchell showed, there is a slight latency, perhaps twenty seconds before light touch evokes markedly increased burning from touch in injury of central origin, whereas the pain of light touch is instantaneous in peripheral nerve injury. This phenomenon is called Mitchell’s Delay. We have found no exceptions to it, but they may exist.
Three neurons are required for a pain signal to go up the cord to the thalamus and brain. At each connection or synapse, there are “interneurons” which have input into the synaptic gap (aka synaptic cleft).
In order to maintain stability (the body favors homeostasis) there are thousands of stimulatory and thousands of inhibitory connections which influence the FREQUENCY of the pain signal, or action potential crossing each synapse. The signal may be dampened (as it almost always is because of descending inhibition by the brain), maintained, or increased (frequency raised). In hypersensitization, the frequency at which action potentials cross the synapse increases greatly, probably because acids form and the vacuoles which contain chemicals at the synapse on either side are themselves acidic. Damping of the firing requires GABA(A) or sometimes other inhibitory amino acids.
Central Pain represents the disabling of the inhibitory wing of the chemical signal balancing apparatus at the synapse. Changes are not limited to the synapse, but excitation also occurs along the entire axonal membrane, which becomes capable of forming a generator current sufficient to initiate an action potential. Partly because the mechanism for axonal excitation is not well known and partly because it makes the discussion too complex, we dwell here ONLY on the action at the synapse. Axonal excitation probably involves an increased number of ion channels floating down from the cell body and implanting in the wall of the neuron extension which we term an axon. Normally, ONLY A NEURON ENDING is capable of generating an action potential. In nerve injury pain, the ENTIRE axon is capable of acting as a nerve ending.
Individual neurons can fire at up to fifty times per second. The combination of inputs from neighboring neurons can reach perhaps 1000 to 2000 firings per second in a nerve (a nerve is made up of many neurons, traveling more or less in parallel). Chemicals released by an injured neuron can recruit uninjured neighbor neurons, which begin spontaneous automatic firing (crossed afterdischarge).
In television, when an electron hits the back of the screen, phosphors are excited and glow. In CP when the action potential hits a synapse, the excitation on the far side of the gap by kinases causes an upgrading of the pain signal, until the thalamus delivers the final punch to the cortex, which registers severe conscious pain.
Since a resting level activity is always present in all nerves, no external stimulus is needed to cause pain. Resting activity comes from the fact molecules are vibrating constantly at any temperature above absolute zerio (-454 Kelvin). The resting frequency of firing is due to the kinetic energy of heat which is present throughout the universe, and of course in first order neurons. The kinetic energy of heat refers to random motion in atoms, with occasional aggregations of charged ions generating sufficient voltage to set off an action potential. The brain receives a steady bombardment of this “noise” from the nerve system. Ordinarily the brain ignores the noise, but in Central Pain, the hypersensitization at the synapse turns the noise into a menace, the agonizing condition of central pain.
When synapses are hypersensitized by the proteins produced by gene mRNA production in the neuron cell body, the response to random noise is exaggerated into a signal of such frequency that the brain reads it exactly as it reads a signal from tissue injury. It is not a pure pain, but very dirty. Since ALL sensory tracts are hypersensitized, there is a mixing of pain signals, which produces a mixed sensation known as burning dysesthesia. This process could also be thought of as collapsing floors in a skyscraper which fall with combined massive weight at ground level. Combined signal from many neurons hits the thalamus with impact.
Since most work to date has been on peripheral nerve injury pain, we are always interested to see studies confirming that the same chemical cascade is present in central pain. Yale scientists have now shown that in central pain, abnormal ion channels increase in the thalamus. This makes the hypersensitization a function of the entire length of the pain pathway and shows that these channels which have been observed lower down in nerve injury are also present in the thalamus in central pain.
Pain chemistry is not particularly creative, since each synapse seems to more or less copycat the prior one. The acids come out to play all along the nerve.
The first order neuron comes up from skin to the dorsal root ganglion, which is a collection of nerve cell bodies just outside the cord. The DRG is a hub for the conscious nervous system, as well as the unconscious or autonomic nerve system. Scientists generally agree that the unconscious nervous system at the DRG may nevertheless create hypersensitization in the conscious pathways. Parts of the unconscious nervous system travel with blood vessels outside the cord and may represent an alternate pathway for signal to bypass severed locations in the cord.
As an action potential enters the cord from the DRG, a signal is transferred to a second order neuron on the opposite side of the cord, which then goes up to the thalamus, where we find the third order neuron. (There are some pain impulses which remain on the same side, but most go to the opposite side).
It can be misleading to oversimplify the travel of pain in this fashion, since each synapse has thousands of inputs from neighboring cells and fibers. However, there is a primary pain pathway and that is what we hope to focus on at this time.
In uninjured nerves, there is a balance of exciting and inhibiting connections. Glutamate or aspartate are the exciter chemicals and GABA or glycine are the inhibitors, depending on which location of the central nervous system is under discussion.
The balance between exciters and inhibitors is upset in CP because the inhibitory inputs are blocked. The result is called “exciter toxicity”, but it can mostly be thought of as the production of fatty acids, which sensitize neurons.
It is believed that the hypersensitization in Central Pain is accomplished by cells adjacent to the neurons which are making the connection. Growth factors released from cells neighboring the neurons, such as microglia (which releases BDNF), block the normal balancing inhibition. It takes no genius to realize that if the damping mechanism is disabled, the human being is in real trouble. We are then talking about a loop with positive feedback, which as all physicists know cannot help leading to more signal. Dr. Patrick Wall pointed out that when we speak of a positive feedback loop in pain nerves we are talking about torture.
Jeffrey Coull and others have shown that BDNF BLOCKS GABA(A), which is the balancing inhibitory chemical at the synapse. Then, the excitatory cascade can begin an unopposed production of pain exciters from the protein factories in the genes of the neurons and microglia and other cells associated with neurons and synapses.
The sensation of pain does not result from a different type or amplitude of action potential, but merely increased frequency of the action potentials (voltage spikes in the neuron). Pain signal is therefore FM or frequency modulated.
The increased frequency is accomplished by large numbers of Nav1.3 ion channels which allow currents (movement of charged ions) across the neuronal membrane, at greater frequency. The ion channels are produced in the cell body of the nerve, located in the DRG, which either implant locally in the wall of the cell body or move down the axon to implant in the membrane of the axon.
When myelin is present, the action potentials may actually jump from node to node along the neuron with great speed, because it avoids the need for so many progressive action potentials marching up the nerve like falling dominoes.
The hypersensitization of CP comes from signal in the slowly transmitting, very thin, unmyelinated C fiber, in which we find the TRPV 1 receptor, discussed at length elsewhere at this site, and linked to CaV2.2 ion channels. However, once the C fiber reaches the cord, it has the ability to spread the pain message to the neighboring A fibers which carry rapid, potent pain messages. The recruitment of A fibers occurs in the cord at the synapse between first order and second order neurons. This has long been known with regard to peripheral nerve injury power.
In the study cited below, Waxman and Hains finally show that the process of production of Nav1.3 FETAL ion channels occurs all over again in the thalamus, with amplification made possible by abnormal production of fetal ion channels, the hypersensitization may also occur in the thalamus itself. This is why patients with stroke near the thalamus often develop central pain, in a fashion similar to CP development in spinal cord injury (SCI).
We have already shown elswhere that pain is largely a process of acidification by certain fatty acids and the kinases which create them, a process which some prefer to call neuroinflammation. Neuroinflammation progressively overcomes the normal chemistry of the nerve pathways. This acidification which follows nerve injury feels like, shock the world, acid. Clinicians have a fancy word for it, “dysesthesia”.
Dysesthesia is perceived as if it comes from just under the skin, but the acid is actually located at the synapses. Tap the knee and the foot jerks. Acidify the synapse and the skin burns.
Hains at Yale has already shown in the DRG and dorsal horn of the cord that in Central Pain, the usual sodium ion channel, the Nav1.8, does not really participate in the neuropathic pain. Rather, a fetal ion channel, Nav1.3 begins to take over in the cord. Now the same process has been discovered in the thalamus.
Waxman and Hains reported in “Fire and phantoms after spinal cord injury: Na(+) channels and central pain”, Trends Neurosci. 2006 Feb 20, that abnormal expression of the Nav1.3 Na(+) channel “within second-order spinal cord dorsal horn neurons and third-order thalamic neurons occurs along the pain pathway after SCI.” They suggest that this change “makes these neurons hyperexcitable so that they act as pain amplifiers and generators.” These researchers now hope to identify molecular targets for pharmacologic treatment.
This is the first demonstration of Nav 1.3 in the thalamus in Central Pain. Our sincere thanks to the exceedingly bright pain researchers at Yale for staying after this. We burn more than they know, and our gratitude similarly is great.