AMPA and kainate are for fast pain, we THINK.

AMPA is the abbreviation for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. This chemical has a specific receptor on the brain side of nerve synapses which is termed the AMPA receptor or AMPA-R. There are actually several forms of the AMPA-R, but that is not helpful here. Traditionaly, AMPA/kainate were the receptors by which cells around the neuron (the glial cells) could upregulate pain signalling in the neurons. However, in the ever more bewildering world of the brain, we now know that both AMPA and especially NMDA signal TO the glia, as well. (See Lalo et al J Neurosci. 2006 Mar 8;26(10):2673-83). Trafficking apparently goes both ways, from neuron to glia as well as from glia to neuron. Once you get the vocabulary down, it gets VERy interesting, since BDNF from glia blocks the ability of GABA to suppress pain.

There is always this double whammy of pain, as if the body is serious about it and if you are going to have chemicals signalling pain, the body do a two-step and block the chemicals like GABA, which damp pain. Nature can be so cruel. You find out just how cruel if you spend a little time talking to people with severe CP. Injured neurons also do not make sufficient KCC2 which is the carrier which brings chloride to the cell membrane to inhibit pain. So maybe it is a three-step. Either way, it really burns. Even clothing and light touch can become unbearable.

NMDA, the socalled “Pain modulator” might be better thought of as just one of the calcium conductance modulators, rather than as a channel specific to chronic pain. [We say this because pain is poorly funded, so much of what we know about NMDA comes from the fact that NMDA is behind the cell injury following stroke (stroke is well funded) and blockers of NMDA are underway to prevent brain injury in stroke to augment the tRa, which already helps prevent spreading brain injury and cell death after stroke] Pain might actually be PERCEIVED NMDA induced injury, while cell death might be UNPERCEIVED NMDA injury, for all we know. Things get pretty hairy, with at least three known phases of the NMDA induced conductances (signalling) to the glia, the early phase not apparently being blocked by Magnesium, which has been regarded as a blocker of NMDA.

Glia are important since they release growth factors which act on neurons, including the brain derived neurotrophic factor (BDNF) which is behind central pain. (See BDNF at this site using search). NMDA is also important in learning and memory, and changes in it in central pain may explain why CP subjects complain of memory problems (hence, the instant article on “CP amnesia”). We do not have sufficient data to allow us to distinguish memory problems in stroke CP, which is on one side of the body, from spinal cord injury CP, which is usually bilateral.

It is now known that bursting of NMDA receptors at a frequency of 10 Hz can occur. Bursting is the dense discharge of nerve firings which show up as kind of a clump of pain signal on nerve tracings. The average individual does not demonstrate bursting from pain, whereas in central pain, nerves in the VPL/VPM nuclei of the thalamus show regular sponataneous bursting which probably correlates with spontaneous burning in CP dysesthesia. Bursting is a synchronous discharge by neurons, whereas the normal situation is random firing of varying frequencies, the frequency being the determinant of how much pain is being perceived.

The bursting pattern of CP would be handy at convincing your doctor you are not faking about the pain, except for the fact that you cannot walk into the office with wires feeding into your thalamus, hooked up to an oscilloscope and signal plotter. The doctor just has to take your word for it. This bursting is what made early researchers feel central pain might be some kind of epilepsy in the thalamus, which led to the trial of anticonvulsants as a treatment for Central Pain. Although not very effective, anticonvulsants are still used for central pain for their ability to quiet the central nervous system. They are about as effective as a cool breeze on a really severe sunburn, which is to say not particularly effective in most people.

Some termed AMPA/kainate receptors as “NON-NMDA receptors” but the discovery of the linkage of NK1 and neurokinin as a non-NMDA receptor and also the action of CGRP as a pain chemical have pretty much eliminated the use of non-NMDA as a term. If you come across it in the literature you will know now what they mean, AMPA/kainate.

Calcium is a driver of the central nervous system. Too much DOES too much, however. You have heard of lockjaw or tetanus, which delivers too much calcium to muscle activating nerves. Calcium can be fatal by forcing the heart into a contraction from which it cannot relax, eliminating the part of a heartbeat where the heart has time to fill with blood. Central Pain is sort of a lockjaw in the pain nerves. AMPA and kainate are two calcium processing receptors (calcium eventually finding its way to the TRPV-1 receptor behind central pain and lethal to the cell if the influence becomes strong enough). AMPA and kainate are made up of similar structural subunits which are receptors for Glutamate, the major exciter neurotransmitter of the Central Nervous System, at least in the cord (In the brain and relating to pain, glycine and GABA are inhibitor neurotransmitters)

Both Glutamate and aspartate (re: NMDS), are two of the very few amino acids (nearly thirty amino acids in humans) which are actually acidic (most actually being neutral or basic). Glutamate and aspartate are involved with pain excitation in ways now being understood.

You have read elsewhere that we attach great significance to this, since pain can be thought of as anything which accumulates acids in the perineural area, (and these acids are perceived of as an “acid burn” in Central Pain dysesthesia). All organic proteins are very sensitive to acidity, so much so that the body has fantastically elaborate systems to keep the body pH at 7.4. The disruption of this homeostatic control of hydrogen ions (acid) in nerves is behind nerve injury pain.

AMPA is spoken of sometimes as made up of any of the GluR1-4, glutamate recpetors type 1 through 5, receptors (although for all practical purposes the GluR1 transmits nearly all the calcium), while presence of GluR5 is taken as an indicator a receptor is a kainate. AMPA and kainate receptors can be difficult to separate because they are quite similar in sructure and function.

It is commonly said that AMPA is responsible for fast pain, while NMDA is responsible for slow pain. This is an oversimplication of the first order. It is true that Calcium flows in less than a millisecond through an AMPA channel, but takes about 25 milliseconds to go through an NMDA channel. (Magnesium ions can upset the normal function on an NMDA channel) However, whether it is one half millisecond or 25 milliseconds this is still very fast. And so it is not surprising that the carefully erected classification of AMPA as being for fast pain and NMDA for slow or chronic pain is beginning to develop holes. For one thing, we now know that AMPA works by activating NMDA receptors, and increasing the calcium in the vicinity of NMDA receptors. We are beginning to wonder if AMPA might be a part of Central Pain after all.

Probably the most shocking article to appear in the literature was by Pogatki-Zahn in Schmerz. 2006 May 11 (Schmerz is German for pain).

After surgery there is allodynia in the area of the incision. To simplifiy a bit, the primary is in the immediate area, and the secondary refers to sensitization to the area outside the vicinity of the incision (probably because C fibers once sensitized, with time, can recruit larger pain fibers which enter the dorsal cord nearby, creating a perception of pain and hyperalgesia wider than the injury area and traveling via nerves devoted to outlier areas of the skin).

Traditional wisdom would have attributed the secondary allodynia to NMDA receptors. To the astonishment of all, the secondary hyperalgesia appears to be due to central sensitization. Even more amazing was the find that NMDA antagonists inhibit the secondary hyperalgesia poorly, cause motor deficits, and supraspinal abnormalities, indicating NMDA is NOT the normal pathway for the commonly observed, garden variety secondary allodynia.

Not very long ago, AMPA was considered to be a calcium channel INTO neurons, moduling fast pain. Instead, the German authors found that AMPA, the supposed fast pain receptor was also actually the mediator of SECONDARY allodynia (hyperalgesia) along with the unexpected finding by Lalo that AMPA signals TO glia. (Again, glia are the nexus of neuron immune function and produce nerve growth factors) This causes us to abandon any preconceived notions and declare that we are still learning. AMPA and NMDA are in the middle of pain, but they are working some kind of shell game that we cannot easily see, since the conductances through these channels has phases that act like tripwires. This is quite important since there recently have been developed some new blockers of AMPA far superior to NBQX (a type of quinoxiline which is the traditional blocker of AMPA). Also, blockers of kainate receptors based on willardine are now being developed.

The scientists are going to whip pain one way or the other, even if they wind up whipping the pain they didn’t think they were blocking and even if their treatment is not directed at the supposed culprit of chronic pain, NMDA.

This information is probably only amazing to pain scientists, but it shows you how much study is needed if we hope to stop pain. A number of the drugs given today attribute their benefit to the blockage of NMDA receptors. If this is not the proper target, no wonder we are having problems coming up with effective treatment.

It is also known now that there are calcium impermeable AMPA receptors which partner with the NMDA receptors. (a number of isoforms of AMPA receptors exist in humans) What this means one can only guess.

At any rate, despite Mitchell’s delay, despite the traditional linkage of NMDA with chronic pain, we are much closer to understanding how the brain daisy chains the various chemical pain pathways together. Central sensitization is so common that it has made the study of pain matters quite respectable and popular. They will stumble across how to solve central pain while they are chasing down central sensitization. The scientists are aiming to find all links in the pain chemical cascade. It is turning out to be rather complicated and there appear to be severe bypasses, wherein if one route is blocked, another will suffice. However, they are in the hunt, and they are going to win. So are we.