As much as we would like to avoid the technical, it will very soon be impossible to explain research to anyone who does not have at least a passing familiarity with what is meant by the NMDA receptor, the mediator at nociceptor synapses of chronic central pain. We introduce terms you will come across later. Once you get the terms, it is not so much worse than figuring out how to download an Ipod, an inborn ability for teenagers which requires sweat and toil for adults.
The NMDA receptor is a heterogeneous complex of the NR1 receptor subunit, combined with one of four types of the NR2 subunits (A through D). There is also an NR3, which coassembles with NR1, but its function is not well understood, except that it seems to originally reside in the endoplasmic reticulum and concern itself with subunit assembly.
It is important to remember in reading this article, that while we include information on both 1) the time of opening of an ion channel AND 2) the strength of the excitatory post synaptic potential (EPSP) of the NMDAR, that work indicates that the kinetics of EPSP do NOT regulate LTP in thalamocortical synapses, and presumably all synapses. See Barth and Malenka, Nature Neuroscience 4, 235 – 236 (2001)
Long term potentiation (LTP) at the synapse (see below), a state of hyperactivity, is a VERY important part of central pain, but so far as is known it is dependent on the COMPOSITION of the NR subunits, NOT the DURATION of the EPSP. Therefore, you should try to remember NR1 and NR2 as distinct, and realize that they have unique functions in the NMDAR and will be researched separately.
In the future, we will be writing of NR1 or NR2 and drugs which impact them inidividually, and there will not be space to explain what we are talking about. We are talking about the building blocks which in various proportions make up the NMDAR. Many drugs are already linked to the NMDAR, For example, iF you use Lyrica (pregabalin), you need to know about the NMDAR both to understand side effects and to determine the most effective medication for your pain. Being highly oversimplistic, NMDAR activity is related to calcium 2+ flux, which can be thought of as knocking out the magnesium 2+ plug in the pore of the receptor, which is made of varying proportions of NR1 and NR2.
However, because NR3A actually is a drag, or reducer, of calcium permeability of the NMDAR, some have theorized that neuronal injury in central pain might involve impairment of the NR3A subunit. Injured neurons not uncommonly are incapable of manufacturing carrier proteins to move molecules around.
This would be similar to “anion reversal” whereby any inhibitory signal is converted to an excitatory pain signal because inhibition requires chloride. Injured cells cannot make enough KCC2, the chloride carrier, so the molecule cannot be moved to the membrane. Based on work by Ehlers, it is thought that the pain function of protein kinase C (PKC) is to place NR1 subunits on the cell membrane surface. Upregulation of PKC in central pain is therefore of concern. Excess NR1 contributes to a chronic pain state.
NMDA, which is present at the presynaptic boundary paases to the postsynaptic active areas, which concentrate around the postsynaptic density (PSD is named for a kind of darkening under the microscope). NMDA associates with a scaffolding in the PSD composed of PSD95 protein and guanylate kinase domain-associated protein (GKAP). Scaffolding proteins in turn allow NMDA to link up with what is going on inside the cytoplasm of the neuron in the endoplasmic reticulum (ER). In the rough ER, RNA feeds the ribosomes and peptides are manufactured. You can review the DNA transcription and later translation of the DNA template via the mechanisms of RNA in any biology text or online. The connection of NMDAR to the ER via PDK95/GKAP helps regulate gene expression, which for our purposes means the production of pain producing chemicals by the genes. For purposes of this article, we shall use NMDA and NMDAR interchangeably.
Infection of CP lab animals with a virus which injects Cre recombinase knocks out NR1 units and this cuts NMDA function by 85% and greatly reduces NMDA related pain. It does not, however, reduce AMPA pain, or fast pain. (see AMPA, using search, at this site) Combinations of various NR1 subunits affects sensitivity to Protein Kinase C, while NR2 determines the open time and empowers ion conductance, eg calcium 2+. Clusters of all NR1 or all NR2 subunits alone do not form into channels, a combination of the two is needed.
In normal cells at least there appears to be a negative feedback of the NMDAR, since NMDA itself reduces the number of NR1 subunits appearing at the cell surface. This may possibly be exploited for therapy through some manipulation of the feedback. Oddly, the reduction of NR1 by NMDA requires calcium.
The N terminal of the NMDA peptide is deficient in Alzheimers. This nearly guarantees some help for pain researchers since the government, which practically starves pain research, is almost fanatical about funding the search for cures for Alzheimer