Fighting NMDA in pain

Researchers continue to search for the mother lode of pain, the sustaining force which drives central pain.

Most readers will know by now that the pain excitatory neurotransmitter in chronic human pain is an amino acid, aspartate. N-methyl-D-aspartate to be exact. The other main excitatory amino acid is glutamate which acts primarily in the spinal cord. Asparate is active in brain. The aspartate brain pathways appear capable of acting in response to their own driving stimuli (thought to originate with thalamic and thalamocortical activity) as well as being easily drawn in to create pain when glutamate is acting up down in the cord. NMDA awakens on its own; or, when signalled to do so by glutamate. Glutamate probably has local pain functions in the brain as well, especially with regard to aversive learning, and to operate in association with aspartate signalling in many brain areas.

NMDA impacts many systems, including memory, so as always we look not only at the neurotransmitter, we must look at its receptor as well. The receptor will have multiple parts and multiple actions. The effect of NMDA on one receptor may bear no relation to its effect on another receptor. The NMDA receptor is very large. Our associates at the Stanford folding lab reported that the NMDA receptor was too large for their computing power to determine its structure. Something this big has many parts and many functions. Short stretches of the receptor are called subunits.

One action which is necessary is binding, to permit the NMDA to attach to or enter (endocytosis) its receptor.

Another action which must always occur is activation. In the human body, another word for activation is phosphorylation. That is because in humans cellular energy is stored as high energy phosphate bonds. When thesse are released from ATP (adenosine triphosphate) an energizing bond attaches to whatever inert chemical is the target. An enzyme helps make the transfer, and such enzymes in the nervous system are known as kinases. Mitogen activated protein kinase (MAPK) is the kinase most often associated with pain and is more or less coupled to the activity of pERK (phosphorylated extracellular signal-related kinase) NMDA works in tandem with pERK, another kinase, to begin to create an acid environment around the neuron. Perineural acidosis (of which fatty acids play a role) is thought to be behind the dysesthetic burning which so afflicts the Central Pain subject. (see elsewhere at this site on arachidonic acid and fatty acid amide hydrolase)

What is a kinase? It is a fuel truck. The kinases are busy attaching high energy phosphate bonds to other compounds. ERK is not a single kinase. There are many similar varieties, ERK1, ERK2, etc., each with targets (subcellular compartments) of its own, often acting in what might be called parallel cascades. pERK operates in areas such as cell excitability and gene expression, which are themselves linked. Again, what is important in neurotransmission activity is not so much the actor as the receptor on which it acts.

When NMDA is the acting agent, it must first be phosphorylated and then must attach to its receptor. The receptor, in turn, must be phosphorylated to begin its action.

Steps in the cell are not random operations, but each one must have its supply of power, which is the electron rich high energy phosphate bond, which is delivered by the kinases. To maintain order, kinases are more or less specific, so they are supplying what ought to be supplied and nothing else. Kinases are NOT a “one size fits all” energy supplier. They are chemicals with a mission.

The NMDA receptor has been divided into various parts, or subunits. Some researchers believe they have found the subunit of NMDA receptor which is responsible for pain. They have named it the NR2B subunit. Not a few go so far as to say that aberrations in NR2B are responsible for the initiation and maintenance of the central sensitization responsible for central pain.

KR Gogas, who is one of the neuroscientists down in “Neuron Valley”, the area of San Diego inspired by the neuro work at Scripps Institute, has written in Curr Opin Pharmacol. 2005 Dec 20 that the NR2B subunit is indeed implicated as possibly the primary factor in central neuropathic pain. He points out that drugs aimed at the NR2B subunit are being developed, and have already been developed, in the hopes of selectively blocking THIS particular result of NMDA activity.

We appreciate the efforts of drug companies to solve the pain problem. Despite the continuing skepticism among some doctors as to whether Central Pain even exists, you can be certain the pharmaceutical firms, long aware that pain relief is number one for revenue, would not be pursuing these matters if it had not been well established that neuropathic pain not only exists, it is a major unmet need for therapy. NR2B blockers are a looming target for therapeutic compounds.