No, calpain is not pain found in California! The science of neuroprotection is in its infancy, but promises to be BIGGG!!! Neuroprotection assumes that continued excessive stimulation of a neuron injures it, so suppressive forces are normally in play. When the “tachometer” gets in the pain red zone, as it were, the neurochemicals such as calpain kick in. Since all CP subjects live in the red zone, calpain should be our friend, but where is it when we need it? Or, does it take more than calpain to stop the runaway pain locomotive which is CP. These questions will shortly begin to form in the minds of those who can answer it.
Glutamate and aspartate are the two primary acidic amino acids whichs drive pain. They are pain neurotransmitters. Glutamate operates more in the spinal cord and aspartate in the brain. Since CP subjects are genearlly capable of having their burning pain EVOKED by peripheral stimulation, and one route for causing CP may be some sort of overpowering peripheral stimulation (although local brain injury can also cause CP) we concern ourselves with both glutamate and aspartate, even though we know that in CP, the brain is doing all it can to turn up the gain on any pain signal coming up through the thalamus and subthalamic nucleus. At the same time, down in the cord, the dorsal root ganglion is going crazy, driving as hard as it can to put pain signal INTO the cord. Completing the torment, the injured neurons cannot inhibit this out of control pain, since injured neurons cannot manufacture sufficient KCC2 to bring inhibitory chloride ions to the cell membrane, to inhibit the action potential. We have one word for this, “Ouch”. Central pain is considered to be the mosts severe pain state known to man. However, scientists are hot on the trail for a cure, and it is assumed an oral blocker of the CaV2.2 calcium channel would end our chronic pain. We already have a blocker of the CaV2.2 channel, the omega conotoxin known as Prialt, or ziconotide (See prior articles on voltage gated calcium channels).
From prior articles here, you may recall that when a chemical signal crosses the synapse, or neuron junction, there are two broad categories of proteins waiting on the other side to be activated. The first, AMPA, modulates FAST pain, or quick pain. The second, NMDA is rather more powerful, modulating chronic pain. Proteins in the body are degraded or dissolved by substances known as proteases. They are widely distributed in the body, which does a pretty good job of tidying up proteins it doesn’t want. Calpain is a calcium dependent protease for the NMDA receptor. Calpain actually degrades the NMDAR (see below). With chronic drive of the NMDA receptor, this protease begins to degrade it. Something similar happens to activated AMPA receptors, but acts through suppression of gene expression manufacturing the AMPA receptor, in particular Glu$2 and GluR3. It is not known why the body is content simply decreases production of AMPA receptors which mediate fast pain, while it actually begins to degrade NMDA receptors with calpain with continued drive by glutamate into chronic pain. The protease calpain is considered to be neuroprotective. It is not clear how it is protecting neurons. Possibly the activation of them causes buildup of local acids, such as arachidonic acid or fatty acids, or enzymes designed to break cells apart, the lysosomes. In any event, neurons have a kind of negative feedback. Since CP subjects do not enjoy the benefit of a negative feedback, and burn continually, without end, one has to wonder if the neuroprotective chemistry is intact.
Keeping in mind that one cannot think of the NMDA receptor as related only to pain (memory is involved also), it is interesting to note that the body knows very well this NMDA can be a bad boy.
From other articles at this site, you will recall that glutamate activates the NMDA receptor. (NMDA is N-methyl-D-aspartate, and NMDAR is its receptor on the far side of the synapse.). This is the prime pathway for chronic pain, through the NMDA receptor.
You also recall that a nerve gap or junction is called a synapse, and that presynaptic activity is different from postsynaptic activity, where the NMDA receptor lies.
It is now known for example that in RAB3 mutant mice the presynaptic aspect of BDNF is blocked, but the postsynaptic effect of BDNF remains intact. BDNF is brain derived neurotrophic factor, one of the “growth factors” which influence gene expression in injured neurons. (see elsewhere at this site on BDNF using SEARCH)
The NMDA receptor is a calcium channel, ie. is very permeable to calcium, Remember, not ALL calcium channels are voltage gated (see prior articles on voltage gated calcium channels). It really cranks up chronic pain, including Central Pain when the NMDA receptor is driven by glutamate from the presynaptic sites. NMDAR has several subunits, 2A and 2B are most important in pain, while 1D is most active during fetal life, where in early development, neurosteroids like pregnenelone are essential for normal NMDA receptor formation, (and for that matter brain formation) and neurosteroid levels may account for certain sex differences in pain perception.
Now we know that the body responds to prolonged glutamate drive by manufacturing calpain. (See Wu J Biol Chem Mar 05). Calpain degrades the NMDA receptor, causing a neuroprotective effect. When calpain inhbitors are administered, the interruption of chrnoic pain does not occur. All of this makes us wonder, of course, if calpain might be inadequate or deficient in central pain. In other words, we wonder whether failed neuroprotection occurs in a neuron which has insufficient calpain. This is not known, but we congratulate the scientists doing this kind of work and hope to hear more about calpain in CP. When we say “more”, we mean “anything” about calpain in Central Pain, this article being the first to query a relation.