All that Sensitizes is not NMDAR

Yes, we are fickle. We just published an article which required some laborious effort to understand NMDA and blamed it for most everything. However, as a prior article here pointed out, there is almost certainly an element of fast, or AMPA/kainate pain, in some central pain, possibly in most who have EVOKED burning dysesthesia.


We have already commented on the dichotomy of NR1 and NR2 subunits in the composition of the NMDA receptor. Keeping that in mind, it is likely that AMPA must also be considered as one more variable in the calculus of central pain.

It may be helpful to reread the article on Fast Pain here at this site, just to remind you that AMPA also sits at the synapse and is a mediator of its own special kind of pain, rapid pain, or what is basically thought of as normal pain.

Actually, there is strong evidence that NDMA pain (chronic or slow pain) and AMPA pain can CONVERGE in central pain.

Both NMDA and AMPA receptors involve the flow of calcium 2+ ions. Because it is possible to block NMDA and still measure current at the synapse, we know that other non-NMDA receptors are involved in pain. What can these mysterious receptors be? Why nothing more than our old friend, the AMPA receptors!

One of the remarkable things about central pain is how much variance is seen once we get beyond the burning pain and the lancinating pain. The other pains can be very, very diverse. This can get to the point where one patient with central pain in very vivid fashion and to an extreme degree, does not believe someone else actually has central pain because the symptoms vary. The highest common denominator is the burning dysesthesia, but the central pains can elaborate to a surprising degree. No doubt, the variety of involvement of various receptors, the permutations and combinations of pathways involved, and the unique gene expression in each individual can impact the ultimate sensory perception of pain.

Not enough attention has been given to evoked pain–the dramatic increase seen when an adequate stimulus is maintained. This is unfortunate since the evoked pain is what makes central pain the most severe pain state on earth. Spontaneous burning is a heartbreaking punishment, but evoked pain can push people to nearly any lengths to avoid. The thought of wearing shoes, in the right CP person, can make them fear and tremble in the anticipation of something so severe from simple TOUCH. One person responding to the survey said they had begun to dread going to church two days in advance beause it meant they would have to wear shoes, and they felt unable to endure it once again. In another person, wearing clothing is regularly possible. In one CP patient, kinesthetic dysesthesia may cripple them up or paralyze them, while in another, visceral bloating may make for constant nausea and a bloating sensation.

Much of the literature negligently fails to differentiate clinically between spontaneous and evoked pain, even though ENTIRELY DIFFERENT chemical cascades may be core to evoked pain, but not spontaneous. This shows we still have a long way to go to get scientists to be precise. This is especially critical for brain imagers who absolutely must get used to the idea that DYNAMIC imaging is essential if they really want to know where the pain signal is being processed. It is necessary to actually evoke the pain DURING the imaging if meaningful results are to be obtained.

Linda Sorkin, PhD at UCSD, has identified a calcium permeable
non-NMDA receptor which can nevertheless cause spinal sensitization. What receptor does she believe this is? It is the AMPA receptor. She also believes there is a third mechanism of sensitization involving MIXED NMDAR and AMPA.

ERK is a member of the mitogen activated protein kinase signalling cascade. When C fibers are stimulated, both ERK and CREB (the cyclic AMP response binding protein, which is a transcription factor, ie. favors translation of amino acids into pain peptides) become phosphorylated, ie become activated. However, according to Sorkin, LESS THAN HALF of the phosphorylation is blocked by blocking NMDAR!. This means alternate mechanisms can be quite important.

Therefore, although you have seen one case of central pain, it does not mean you have seen them all. This becomes patently clear in reviewing the surveys. We again thank all those who have taken the time to complete the surveys. They have proven remarkably reliable, and science can only catch up to what humans have to say about central pain. One by one, the pieces have fallen into place to validate what the respondents have told us about what central pain is really like. There is still a distance to go, but the nearly one thousand people who have completed the survey have done themselves and us a great service by allowing us to see more clearly, to pixellate to a higher resolution, what the picture of Central Pain should really look like.

Whether AMPA proves to be at the heart of EVOKED central pain while NMDA sustains spontaneous burning dysesthesia, we do not know, but we do know these matters should be kept in mind in any investigation.