There is probably some fast pain in CP

AMPA/kainate or kainic acid/AMPA, as it is sometimes called, orginally was thought to be exclusively part of fast pain and therefore not to be part of central pain. However, since A/K does participate in excitotoxic injury, fast pain may be a component of CP. Opiate production is responsive to excitotoxic injury which leads to either fast or chronic pain chemical sets.

Although central pain dysesthetic burning has almost come to be synonomous with Mitchell’s Delay, which is used to differentiate peripheral nerve injury pain from that of central origin, it is worth noting that many with CP have “sharp allodynia”, with no delay whatsover. (“Delay with overshoot” is specific for spinothalamic tract injury and in the context of sharp allodynia refers to an elevated threshold for pain, which when reached, overshoots all out of proportion)

The safety pin challenge was in fact the favorite method of John Bonica to diagnose central pain. A poke with a safety pin gave responses in Central Pain patients all out of proportion to the light pin prick. With our broadened understanding from the surveys, which were in fact encouraged by Bonica, we now know that a positive safety pin challenge test is indicative only of ST damage. There are many with CP whose manifestations may be limited to posterior column pain. Nevertheless, it has been suspected since Bonica’s time and earlier that there IS a component of fast pain in CP. Here we review laboratory evidence for the same.

From past articles you are aware that under existing theory, at the far side of the synapse, AMPA/kainate is thought to be a receptor keyed to fast pain, while receptors awakened by glutamate are more likely to be associated with chronic pain.

We have also questioned repeatedly how much impact opioids have on chronic pain in CP, suggesting that pain carried in the posterior columns of the cord (lemniscal pain) was much more likely to respond to opiods AND to other drugs than was pain carried in the front of the cord (spinothalamic tract pain). This is based on survey results here at this site. The data confirming this have not changed over ten years.

A consequent question would be whether opioids made by the body were even aimed at chronic pain. A way of testing for the association was conceived by Abraham, McGinty, and Brewer. See Neuroscience. 2001;104(3):863-74.

Glutamate receptors formed in the course of metabolic processes by cell action are known as metabotropic* Glutamate receptors or mGluRs. They can be thought of as reflecting a response to glutamate induced signalling for chronic pain.

You will recall that the genes in DNA code for messenger RNA, which travels from the nucleus to the cytoplasm where protein synthesis occurs in several steps including assembly of amino acids by ribosomes. Messenger RNA, which leads to amino acid/peptide formation actually has several manifestations both inchoate and maturely developed. Certain of them result eventually in the body’s manufacture of endogenous opioids, the famous endorphins.

Abraham’s study had to do with early precursors of endorphins preproencephalin and preprodynorphin. Encephalin and dynorphin are opioids produced within the body in response to pain. Abraham also included in the study the injection of mGluR activators(mimics of mGluRs) into spinal cord.

The approach was to induce excitotoxic injury in the cord. This is similar to what happens in Central Pain from the profusion of pain exciter chemicals manufactured by the gene protein factories in response to nerve growth factors, such as the NGF which results in BDNF in the glia around injured neurons, which then blocks GABA(B), a pain inhibitor, and leads to central pain.

Central Pain is itself a combination of excitotoxic injuries, which find their way to the thalamus. Many of the steps in developing central pain involve the formation of acids around the nerves. These acids include derivatives of prostaglandin related arachadonic acid, fatty acids, etc. Acids have a large effect on the way ion channels operate and affect the currents flowing in pain nerves. To understand the power of it, you must consider the entire human body as a battery. Really severe derangement of the pain apparatus is possible.

In their study, the scientists used quisqualic acid or proprionic acid as well as mGluR activators to induce excitotoxic injury in the cord. They also studied attempts to reduce the area of injury by later comixing exciters with blockers to the insulting agents, specifically NBQX (blocks AMPA kainate) and AIDA (blocks mGluRs)**.

Both spontaneous and evoked pain behavior was noted and areas of injury from cord injection included not only the cord but also the brain (cortex).

Thus, this excitotoxic injury truly resembled the situation in central pain.

The authors concluded that BOTH AMPA/kainate and mGluR were involved in production of opioids to fight pain, but that mGluR was more responsible for excitotoxic injury and long term pain behavior in the rats. Thus, we will need more than just opiates to control central pain.

Strangely, NQBX did not reduce opioid production in response to quisqualic acid injection, while AIDA reduced it in both cord and brain and in response to both quisqualic acid and mGluR agonists. Again, this points to mGluRs as evoking both the greatest damage and the greatest opioid response in excitotoxic injury.

The scientists agree with the survey, in a manner studied independently. Opioids probably are produced with both fast and slow pain. Central Pain has both a spontaneous and an evoked component, at least so far as the ST burning is concerned. However, the prolonged impact of mGluRs suggest that opioids alone will not be enough to stop central pain. The main increase in damage was at the epicenter of the injection site with mGluR agonists. Although CP is an incomplete injury, there may be a focus of rather marked injury at the heart of it. This can only be seen histologically, by cell dissection and study, not by any imaging technique, such as MRI.


*metabotropic refers to a type of receptors which are coupled with G proteins. G proteins are “receptor-coupled proteins that bind guanine nucleotides and activate intracellular messenger systems”.

A nucleotide is “any of various compounds consisting of a nucleoside combined with a phosphate group and forming the basic constituent of DNA and RNA.”

A nucleoside is “any of various compounds consisting of a sugar, usually ribose or deoxyribose, and a purine or pyrimidine base, especially a compound obtained by hydrolysis of a nucleic acid, such as adenosine or guanine.”

A purine is “a double-ringed, crystalline organic base, C5H4N4″

A pyrimidine is “a single-ringed, crystalline organic base, C4H4N2″

(These definitions are derived from See that site for more complete information).

**Spelling it out, the metabotropic Glu R blocker used, AIDA, is (RS)-1 aminoindan-1,5-dicarboxylic acid) while the AMPA/kainate blocker used, NBQX, is 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline.