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Comments from the Lager Man – is NMDAr upregulation 4ever

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A little while ago, Paul Lagerman said this:

“….  I was speaking to a colleague of mine who is a pain specialist and we were discussing central sensitisation.  As I understand it there is a genetic change in the cell nucleus which causes an increase in the embedding of NMDA receptors in the cell synapse, oh that’s already complicated writing that??  This is permanent, so if it is a permanent change and not reversible then how is it possible that this can be modulated and information that is coming from that synapse to the brain will not set off the pain signals??  Is it down to reconceptualisation of the information coming to the brain from the synapse, as in are we training the patient that although they may be getting an increased stimulus we have trained the brain to reconceptualise the information as in the brain has final say?? Phew, that was hard but actually after having read that again that kinda makes sense if the brain has final say.”

Great thoughts I reckon. I have a couple of responses to The Lager Man’s excellent pondering and I thought it would be worth making a post out of it because it touches on some pretty common questions.  First, some background – there is pretty compelling evidence from animal studies that persistent noxious stimulation leads to upregulation of NMDA receptor expression (here is a recent review of this [1]).  Don’t freak out – this means that, as The Lager Man suggests, the spinal neuron that carries danger messages to the brain increases its manufacture of the receptors that make that neuron responsive to incoming danger messages from the tissues (AND to descending facilitation, but you can forget about that for now if you like).  It is a bit like there is a ‘Production Rate’ knob in the nucleus of the spinal nociceptor that flicks up a level if the spinal nociceptor is sufficiently active for sufficiently long .  I would contend that there is not compelling evidence that this change in Production Rate is in fact permanent. This view is based primarily on clinical evidence and short-term animal follow-ups. It is more or less impossible to get long-term animal follow-ups because it is not ethically sound to keep an animal once they are upregulated to the extent that putting their foot on the floor hurts.  That is, the animal is put out of its misery.  It makes more sense to me that it is NOT permanent – the knob is turned up as an adaptation and it strikes me as far more sensible that the knob will turn back down again if we can induce the appropriate conditions to make it adapt in this way.  That NMDA receptor expression can be both upregulated and downregulated is extablished (eg Scheetz & Constantine-Paton [2]), which is in line with what we know about biological adaptation in general.  Obviously, to normalise the NMDA receptor Production Rate is not a trivial task.  It brings me to The Lager Man’s final pondering – “are we, then, simply trying to get someone’s brain to reconceptualise the incoming nociceptive information all the while accepting that the spinal nociceptor is now and forevermore upregulated, or are we trying to actually turn the NMDA receptor Production Rate Knob back to its original setting?” (Lorimer’s paraphrase). I think we are trying to do both and the best way of ultimately achieving the latter is to first conquer the former.  As a quick proviso here though, we KNOW that the spinal nociceptor can go bezerk and not be associated with pain if the brain is actually of the view that the spinal nociceptor is mistaken – that things are actually not dangerous. So, to convince the brain of this is the first goal, lofty as it is. To take this to the next level, to rewinding the NMDA receptor Production Rate knob, I think we need to inhibit the spinal nociceptor.  There are two inputs that stimulate it – incoming nociceptive input (or incoming input of any kind in the case of C-fibre death – our task is more daunting in this scenario) and descending facilitation.  Incoming nociceptor input can be modulated in a variety of ways – tissue health, anaesthesia, nerve blocks, injections etc etc. If you are a structural-pathology paradigmer then this is your bread and butter.  Descending inhibition is all about getting the brain to conclude that the tissue is not actually in danger. Which brings us back to the first goal, lofty as it is.  I could ramble for a year on this, but you will go over your download limit.  In short – as The Lager Man reflects – ‘..the brain has the final say’.

References

ResearchBlogging.org [1] Petrenko, A., Yamakura, T., Baba, H., & Shimoji, K. (2003). The Role of N-Methyl-d-Aspartate (NMDA) Receptors in Pain: A Review Anesthesia & Analgesia, 1108-1116 DOI: 10.1213/01.ANE.0000081061.12235.55

[2] Scheetz AJ, & Constantine-Paton M (1994). Modulation of NMDA receptor function: implications for vertebrate neural development. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 8 (10), 745-52 PMID: 8050674

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