Getting Pain Straight, Thanks to the Insane, the Stroked out, and the Cardiac impaired

Scientists tend to bypass pain research such that they are setting themselves up for a big surprise when they study NMDA. They will stumble across us sooner or later, just when they least expect it. n-Methyl-D-ASPARTATE or NMDA is the receptor on the brain side of a nerve synapse which must activate in order for chronic pain to develop. Central Pain is one of these chronic pains which is driven by NMDA receptors. Aspartate, like Glutamate, is an acidic amino acid, and hence a pain exciter. Glycine, like GABA, is a pain inhibitor. Yet, mysteriously, glycine appears irrevocably linked with NMDA–this bears investigation. No money, no problem, glycine/NMDA are part of heart attack injury and stroke brain injury. The heart and brain are considered research money worthy even if pain is not.

Basically, the NMDA receptor, the chronic pain receptor on the brain side of a neuronal synapse, where nerves meet, has a glycine part. (Glycine is a pain inhibitor, whereas glutamate is a pain exciter.) The glycine site on NMDA is sometimes referred to as glycine/NMDA, although it is only one part. In order for NMDA to excite, to the glycine part MUST be bound glutamate AND a coactor, d-serine, an amino acid which comes from the glia (astrocytes) around the neuron. (See eg. Panatier et al Cell. 2006 May 19;125(4):775-84)

Additionally, Adam et al, studying C fibers, have shown in Neuropharmacology. 2006 May 18, that HA966, a glycine site specific NMDA receptor antagonist (inhibitor) markedly increases response to morphine and reverses morphine tolerance in those in whom morphine does not work. Getting interested? You ought to be. This is core stuff.

Don’t focus on the big words. Just realize this is all going on inside you, and is part of every moment of pain you feel as part of your Central Pain. NMDA is beating the stuffing out of you, nonstop.

As the readers here undoubtedly know by now, the NMDA receptor is very important to pain. It is also important to memory and any number of other things, one of them being the tissue damage which occurs with ischemia, as in stroke or heart attack, which are very heavily funded.

The problem is that NMDA researchers forget pain. Pain is very, very complex, and it seems unnecessary to most to wade through all the pain kinases and fatty acids just to study NMDA.

This is not all bad, since as they forge their way ahead on NMDA, they will uncover valuable material for pain. This is not unlike the researchers who studied NO, or nitric oxide, as a possible cure for impotence (Viagra, etc.), only to find out that NO is an important neurotransmitter, which has a role in pain pathways. Who would have thought erection research would illuminate pain. Furthermore, Viagra gives a headache to Central Pain patients with involvement of the quintothalamic tract (the descending pain tract of Cranial Nerve V, which goes down into the cord). What is Viagra enhanced NO doing to pain nerves? Curious minds would like to know.

We have already published an article here on central pain in schizophrenia, where it is known as “cenesthetic” pain, especially in the German literature. We could just as easily call it Schizophrenic central pain, since those who have written the definitive articles agree with us on this point and have taken pains to let us know they agree. If you were a betting person, you would think then that schizophrenics have some overactive NMDA receptors. Yet, surprisingly, Lindsley and others have demonstrated UNDERfunctioning of the NMDA receptor in schizophrenia. What is not resolved is WHICH action is affected and WHETHER this causes schizophrenia. The explanation probably lies in the glycine site, which is required to function properly for physiologic behavior of glutamate.

It is very interesting that if you administer a glycine site specific NMDA blocker called phencyclidine, it causes psychotic episodes, and if by comparison, you administer either glycine or d-serine, it will help ease psychotic symptoms in schizophrenics. See Pietraszek et al Amino Acids. 2006 May 15

Konradsson et al have shown in Synapse 2006 May 19;60(2):102-108 that inhibition of the primary glycine transporter, GlyT-1 STIMULATES the activity of Glutamate, a pain exciter. This is the interesting case where the blockade of an inhibitor stimulates the major CNS pain exciter, even though existing theory says glutamate must have glycine active to affect NMDA. Since injured neurons are notorious for underproducing transporters, could it be that glycine blockade through lack of a trnsporter makes glutamate go wild in our pain neurons? There would have to be a side mechanism going on, but that is not unlikely.

Smith et al in Bioorg Med Chem Lett. 2006 May 23 have authored an interesting piece entitled “The synthesis and SAR of 2-arylsulfanylphenyl-1-oxyalkylamino acids as GlyT-1 inhibitors.” The background is that recently scientists became aware that there was a special part of the NMDA receptor which is a co-actor with glycine. On the one hand, blockers of glycine were studied in an attempt to stop spreading damage after ischemia.

The problem in the past was that the most promising glycine blocker, ACEA-1021, tended to crystallize in the urine and damage the kidney. However, a more water soluble blocker, ACEA-1416 has now been produced. (see Cai,Curr Top Med Chem. 2006;6(7):651-62)

This means the glycine/NMDA receptor will soon be studied more intensively, and ACEA-1416 will certainly be evaluated for its ability to stop pain. EpiCept, the company Cai works for is well aware of the potential value of ACEA-1416 as a neuroprotectant.

Brown and Krupp have published the hope that inhibition of NMDA receptors will stop pain. (this is quite likely true, once we know WHICH receptor to block).

However, we have the situation of schizophrenia where others are attempting to enhance glycine and thereby crank UP the NMDA receptor to HELP schizophrenia. If schizophrenics are prone to cenesthetic pain, and have lousy glycine/NMDA receptors, there are some obvious connections to the fact many schizophrenics develop nerve injury pain. Glycine, (an inhibitor), is CARRIED to and paired with the NMDA receptor (an exciter) and so the primary carrier of glycine is being studied along with all the rest, (see Smith’s article cited above).

You need not worry about these apparent conflicts. They merely reflect the fact that some scientists are targeting glycine/NMDA receptors without considering why central pain behaves as it does. The researchers cannot help but open up information that will benefit CP. NMDA has MULTI functional receptors. As each one is fleshed out, we will learn more about which are relevant to pain. We must view this research with gratitude for the hard work, no matter how it is funded. Heart and stroke get lots of money. I never get asked at WalMart to donate to Central Pain research but I do get asked to donate to the American Heart Association.

NMDA is related to neuroinflammation, which is related to pain. In the end, pain patients are the stepchildren of research, as we have always been, despite there being more with pain than ANY OTHER MEDICAL COMPLAINT. The leftovers from other research will help us because there IS a dedicated core of pain scientists who watch what comes out in other areas and apply it, even if other areas do NOT return the compliment.

We must be patient. The war against other terrors is on, and our own enemy will be caught in the dragnet. Don’t give up.

In the meantime, all you erection researchers, could you take a moment and consider pain? Solving pain might make you more money than solving embarassment.