We continue an adaptation of the materials provided to painonline by Joseph McGivern, reflecting research by himself and Stefan McDonough.
In prior parts, you have learned that the voltage gated Calcium channels are important in pain. You also have an idea how they are named, according to the building blocks, or subunits which are placed around the basic building block scaffolding of the channel, the alpha 1 subunit, which assembles as groups of four, and is manufactured by the genes of the neuron and assembled into channels via the usual mRNA, ribosome, protein factory route, followed by assembly in the neuron and migration to the neuronal membrane.
These things, these little channels, are real, and you live by them, but you have more of them than you need, so your pain nerves are TOO sensitive. Because the nerve growth and repair factors are out of control in nerve injury, you also make fetal sodium channels, the Nav1.3, which other people without Central Pain do NOT have. (Normal people have Nav1.8, just as CP people do, but Nav1.8 does NOT participate in Central Pain). The fetal Nav1.3 ion channels are real also, are not psychological, and they make you hurt. Think of the channel as a very long docking station for calcium 2+ ions, which moves the calcium across the membrane, at a rate of its choosing, a rate which is controlled by protein kinase C and related chemicals.
The calcium channels and fetal sodium channels set up conditions for the cocking and firing of an action potential (the chloride channels help AIM the firing of the neuron toward inhibition, rather than excitation, but injured neurons cannot manufacture the chloride carrier, so everything is excitation, no inhibition–that is why it hurts so much). To review chloride use SEARCH for J. Coull, at this site. If you think of an automatic rifle which has gotten stuck in firing mode (a common motif in slapstick comedy, such as the Three Stooges), you understand a little about what is happening in the pain neurons with central pain. A car engine can also become so hot that it continues running even when the ignition is turned off. This is known as “dieseling”. Central Pain is “dieseling” of the pain apparatus, as it were. The neurons are just too hypersensitive to quit firing. Funny in the movies, tragic in real life. Because the nervous system really pays attention to pain, the constant barrage from C fibers recruits surrounding alpha pain fibers (not to be confused with the alpha subunits making up the calcium channels) and the CP process is off and running.
“Encding” refers to the amino acid sequence which is written for by a gene, the first step in protein assembly. N-type calcium channels encoded by the CaV2.2 gene are currently the most attractive targets for pain therapy since they are known to be involved in Central Pain, and blocking them should not impair heart function, the heart also requiring calcium channels to beat. Ziconotide has definitely been shown to block the N-type channel, and is also analgesic in humans. This is very hopeful, but must be administered via the spinal fluid, because small peptides tend to be degraded by stomach acid, (by comparison, acidity from cytokines and fatty acids perhaps underlying some of the peptide dysfunction in nerve injury pain).
The blockbuster drug we are hoping for would be an ORAL blocker of the N-type calcium channel. There is also evidence that blocking the T-type calcium channels would block pain, but research there is still just beginning. CaV2.1 is known to play a role in migraine and so is part of the pain cascade, at least in blood vessels. Although the alpha-2-delta subunit is merely an add-on to the main channel gates, the fact that it binds both gabapentin and pregabalin, shows that a treatment aimed at subunits and auxiliary subunits could potentially bind more than one variety of channel.
Although CaV1.2 is considered off limits since it drives the heart, modified dihydropyridines may be able to bypass CaV1.2 channels and have an action to decrease pain. CaV2.1 is expressed strongly at the neuromuscular junction and in the cerebellar Purkinje fibers, hence the name P-type calcium channel. Blocking of CaV2.1 would be expected to interfere with control and strength of bodily muscle activity. The effects of CaV2.3 blockade in mice is subtle, so interest remains on those channels.
In the next part, we will look more specfically at CaV2.2 and will note that they affect release of CGRP, Substance P and glutamate, all of them big players in the pain lineup. Since Takhshid’s article in Sept 2004 Brain Research, which showed that Nitric Oxide inhibition blocks release of CGRP, a known pain player, we have a rational link between NO and the CaV2.2 channel. (Because we have received comments that some with CP experience severe headache with Viagra, which increases NO, we continue to feel the surveys are vital information). We will also touch on the fact that the alpha-1 subunit may be spliced together with itself and with auxiliary subunits in at least ten ways, making genetic variation a possibility and raising the question of why some, but not all with spinal cord injury get central pain. Splicing does affect function and physiology, but since ziconotide seems to block them all, there is reason to believe an oral blocker should do the trick to end central pain, or at least control it.
AND TO ALL THE SCIENTISTS WHO STUDY THESE MATTERS, WE SAY THANK YOU, AND BY THE WAY, CHANGE THE CHANNEL, QUICKLY IF YOU PLEASE.