A very important concept is that injury spreads. This happens at a cellular level due to release of chemicals from injured cells into surrounding cells. It is surprising how toxic materials in the body become once they are out of place. Blood, for example, is very toxic outside the blood vessel. Blood clots to the lung do not kill people, but the spreading of chemicals released FROM the clot does kill people. Now we are beginning to understand how spreading injury operates in injured pain nerves. Neighbor neurons are reprogrammed to make exciters, as if warning the brain of pain is the main duty. When glutamate leaks out in cell injury, havoc occurs.
Every doctor knows that with massive muscle injury, the release of myoglobin typically kills the kidneys. What doctors may not know is what injury to nerve cells does, nor how the whole process operates. Once again, we revisit “neuroplasticity”. In this case, we do so with regard to glutamate response and spreading injury to pain neurons. Dead neurons do not give us pain, but live cells injured by the released chemicals give us central pain.
As you have already read at this site, NMDA is very much involved in the maintenance of CHRONIC or slow pain. NMDA’s action is dependent on Calcium and Glutamate. Please review the articles here at painonline to refresh your memory on how this happens. You may also wish to review some of the material on CREB (cAMP response element-binding protein)* Basically, too much glutamate, under the influence of Ca++, excessively activates NMDA receptors. Using cyclic AMP as a second messenger, NMDA causes synaptic plasticity.
Wang H (a physiologist with our old friends at Toronto) et al in J Biol Chem. 2006 Nov 22; “Genetic evidence for adenylyl cyclase 1 as a target for preventing neuronal excitotoxicity mediated by N-methyl-D-aspartate receptors” showed that adenylyl cyclase 1 and 8 (AC1,AC8) are the major calcium stimulated adenylyl cyclases in the central nervous system. BOTH of these adenylyl cyclases relate to both PAIN and MEMORY. Aversive learning is VERY important to the brain.
Wang showed that the “excessive activation of N-methyl -D-aspartate (NMDA) receptors by glutamate” results in glutamate-induced neuronal excitotoxicity. NMDA is a sleeping giant, which usually stays out of the way in acute pain. Awakened, it can be a real terror.
Glutamate is so excitotoxic that it induces cell death in cultures of neurons. Death is about as excitotoxic as you can get.
However, “genetic deletion of AC1 significantly attenuated neuronal death induced by glutamate in primary cultures of cortical neurons…”, whereas AC8 deletion did not produce significant effect. AC1…contributes to intracellular cAMP production following NMDA receptor activation by glutamate in cultured cortical neurons.
The importance of of AC1 does not stop there. (Please review the role of CREB in the cascade of pain chemicals below). Wang also showed that “AC1 is involved in the dynamic modulation of CREB activity in neuronal excitotoxicity.”
When Wang created mice genetically knocked out from producing AC1, cortical lesions from glutamate injections were significantly reduced in size. Wang feels strongly that AC1 blockade may serve as a therapeutic target for preventing excitotoxicity.
These studies show how important it is to keep the pressure on Elias Zerhouni at NIH and on our elected officials to fund more pain research at NIDCR. We cannot leave everything to our Canadian friends, who have shouldered more than their share of pain research over the past several decades. AC8 knockout does not affect pain. It is quite possible that blockade of AC1 without blockade of AC8 may stop glutamate excitotoxcity without affecting memory to any great extent. Considering how much pain and suffering central pain subjects may experience a LITTLE loss of memory might not be such a bad thing.
We express our thanks to the wonderful team of pain researchers in Toronto, mostly progeny of Ron Tasker. What a debt we owe these people.
Creb binding proteins are transcription factors which can bind to short sequences in DNA known as cAMP response elements. The result is to increase or decrease AC1 and thereby increase or decrease the transcription for certain genes. This is really what “plasticity” is all about.
In most cases of CREB sequential action, some protein messenger attaches to the surface of a cell. This activates a receptor specific for the protein messenger, which causes release of a SECOND MESSENGER, ie cyclic AMP or Calcium2+, which then activates a PROTEIN KINASE. Mitogen activated protein kinase is the main one we are worried about in chronic pain. MAPK travels to the cell nucleus. Then, in the typical (somewhat simplified) sequence of events what follows next is: a signal arrives at the cell surface, activates the corresponding receptor, which leads to the production of a second messenger such as cAMP or Ca2+, which in turn activates a protein kinase. Remember that kinases supply high energy phosphate bonds which act as batteries to power chemical reactions.
This protein kinase (mitogen activated protein kinase is the most important for chronic pain) moves to the cell nucleus, where it joins with a CREB element which then binds to a CREB binding protein which activates it. Using what is known as a “leucine zipper” CREB attaches to the DNA and turns genes ON or OFF.
If you follow this pathway down from transcription, you will know what neuronal “plasticity” really means, and understand how plasticity UPREGULATES NMDA activity (by increasing transciption of exciter genes). You will also understand what we mean by “cascade of pain chemicals”.
The real problem begins with AC1, which it would seem nice to block, if possible. To you, upregulated plasticity means longlasting, big time pain.