We want our normal neurons back, or else to stifle “wannabe” neurons that hurt. It is hard to find an article on brain science without the word “plasticity” in it. Plasticity in this setting means changeability or modulation. Memory itself represents plasticity as new connections allow formation of memories. These connections also facilitate chronic pain. The pain song goes on, long after cells which died are gone, via connections in remaining injured cells, which perpetuate and even amplifiy the pain message. This kind of “growth” we can do without.
There are typically three nerves or neurons which connect, end on end, at nerve junctions, or synapses, to carry a pain message to the brain. If we follow pain from foot to brain, this is the typical pathway.
1. From foot to dorsal root ganglion. (FIRST ORDER NEURON)
The cell body of the peripheral neuron is in the dorsal root ganglion, which is a round structure just outside the spinal cord. The neuron has a long extension, known as the axon, which leads to the skin. The nerve ending may be specialized, as in the big, rapid, A fibers, or it may be “naked” as in the case of slow, small diameter C fibers, which carry long lasting pain.
2. From dorsal root ganglion to the proper position in the cord. (SECOND ORDER NEURON)
The route for this neuron may go across the cord to synapse in the front at the spinothalamic tracts, or it may stay at the back of the cord and synapse with the posterior columns, long tracts which run up the cord.
The synapse is a physical gap or space between two neurons, such as between first and second order neurons. A synapse is also a connection between neurons of the same order. The signal is carried across by chemicals released into the gap, which then act on chemicals at the far side. Cells which “coach” or influence the signal are known as INTERNEURONS, but the actual pain fibers can also “coach” each other. For example, C fibers reaching the cord can enlist the big, powerful A fibers and recruit them to send out a pain signal.
(This is what happens which capsaicin is injected. The activated C fiber goes to the cord where it recruits A fibers to fire as well. This is called “secondary allodynia” and refers to the fact that A fibers will transmit enhanced pain message from skin, even beyond the area where capsaicin is injected)
Most of the modulation in nerve signal occurs at the synapses. The substances which act at the synapse may come from the neuron itself or from cells AROUND the neuron such as the glial cells.
3. From cord to thalamus. (THIRD ORDER NEURON)
The thalamus is the sensory relay for the body. It sits more or less in the center of the brain, about straight back from the eyeballs. There is a thalamus on each side of the midline, so technically they are thalami, but by convention, both are spoken of as the thalamus. The VPL(body) and VPM (face) nuclei of the thalamus (collections of nerve cell bodies) receive pain signal and send it on with software it creates fpr it on the fly to the cortex, or gray matter.
Pain signal headed for the thalamus may also go to small structures near the thalamus, such as the subthalamic nucleus.There are several brain centers which receive pain signal from the thalamus, including the postcentral gyrus, part of the parietal cortex, and the insular cortex. (See Dr. Francis Crick’s article at this site indicating the insular cortex as responsible for the “painfulness of pain”.)
We do not include here discussion of PAIN INHIBITION pathways which lead down FROM the brain to suppress pain signal, such as through interneurons in the cord. (See eg. the article at this site on the PERIAQUEDUCTAL GRAY, and also Dr. Carl Saab’s article on the VERMIS)
Nerve cells connect with many other nerve cells through tiny connections, which also carry the name synapse, because there is a gap. Growth and connections determine how the nervous system develops and what it recognizes. The typical neuron has THOUSANDS of synapses, so there is tremendous input going on with any signal going to the brain.
The amount of active chemistry affects the formation of NEW synapses, which are favored by growth factors, such as BDNF. Cells in the spinal cord also have many connections or synapses. Some cells in the spinal cord are interneurons, which serve to influence connections of pain fibers. What actually goes forward in the pain pathway is the SUM of input from many sources, both excitatory and inhibitory. There is a tremendous amount of noise in the system, so most of hte work the brain does is to inhibit signal.
When a person has a test called the somatosensory evoked potential, a computer reduces noise by taking thousands of readings and averaging them together, to reduce noise. The brain is more subtle and has ways of shaping a signal to make sense of it. such as edge sharpening in the visual pathway to allow ready identification of objects by their outline BEFORE we actually see them.
Pain Inhibitory signals involve the chloride ion channel. Coull has shown that injured nerves lack the protein, KCC2, which carries chloride to the cell membrane. (See Coull’s contribution to this site, using SEARCH) The apparent result of this is that any cell so injured will have any inhibitory impulse converted to an excitatory one.
The cell signal has a defective chloride switch, which prevents the signal from being inhibitory. The inhibitory signal which the brain would like to send is derailed with the failure of the chloride ion channel. The chloride switch is where GABA exerts its effect (see article on GABA, at this site). Without GABA, you are in big trouble, but you already knew that.
Among the substances which become involved at the synapse are the so called “growth factors”. These influence cellular repair, connection to other cells, and growth. More specifically, they regulate the chromosomes of a cell so that the gene protein factories write for more or less chemical to influence activity and change at the synapse.
If synaptic connection points in a neuron are injured, and only excitatory signals go through, attempts at repairing those cells is productive of pain excitation and pain exciter chemicals, because the inhibitory chloride channel does not work. Any repair would only be making the pain worse.
There are four major growth factors in pain.
1. GDNF Glial cell derived neurotrophic factor.
2. TNF Tumor necrosis factor (See articles on GABA and CREB at this site)
3. ADNF Activity Derived Neurotrophic factor (See at this site, using SEARCH)
4. BDNF Brain derived neurotrophic factor. (See also elsewhere at this site).
Synapses form to strengthen and solidity certain messages under the influence of growth factor. It is obvious that overproduction of growth factor could hypeenstize pain pathways. In Sept 04 Growth Factors, Binder et al discuss the effects of BDNF on synaptic plasticity, or remodeling. He indicates that synaptic change. or plasticity, secondary to BDNF may be largely responsible for the alterations which lead to long term neuropathic pain.
It is hoped further research on BDNF, such as is being conducted at UCSF, will demonstrate ways to avoid Central Pain.