Blockbuster Article on Central Pain

How smart ARE these guys? We already have been blessed with an article just for painonline.com by Jeffrey Coull on chloride- ions. Now, Coull et al have completely blown away the pain world with a new finding published in Dec 15, 2005 Nature. The Canadians are already staffing the Johns Hopkins Neurosurgery department. How far ahead have these people gotten?


There is nothing wrong with Jeffrey Coull except that he is so smart that he speaks in terms that send the rest of us scrambling to our engineering textbooks. Coull has already shown that failure of the choride carrier converts ALL action potentials in pain nerves to excitatory ones. The chloride carrier KCC2 is produced in insufficient quantities by injured neurons, such as in Central Pain.

Since Coull has once again published what is likely the most significant article on central pain this year, we define a couple of terms for you. An anion is an ion attracted to the anode which is positive, which means an anion carries a NEGATIVE charge, since negative ions are attracted to an anode, the positive end of a battery.

Chloride is the major anion of interest in pain. What Coull et al have shown is that Brain Derived Neurotrophic Factor (BDNF-see elsewhere at this site on BDNF, using SEARCH) is stimulated by ATP (adenosine triphosphate-discussed elsewhere here for its role in pain) to communicate with its RECEPTOR, which is known as trkB. Blockage of the ability of GABA-A to link with its receptor results in what Coull has formerly termed “anion reversal” and reverses the normal effect of GABA. Anions are normally inhibitory of action potentials and of pain. Coull has focused for some time on the mechanism of how anions could be made to be excitatory. Now we know. His work is becoming core to understanding how pain nerves operate.

Gamma amino butyric acid (GABA, a blocking counterfeit of glutamate, the big exciter of the CNS) is the major pain inhibitor of the central nervous system. Its impairment could obviously allow the systems normally in place to prevent sensitization of pain nerves from functioning. The location of the activity Coull is studying takes place in Lamina I, the very most superficial layer of the spinal cord (see elsewhere at this site about Rexed Lamina I and pain) Layer I is called the “marginal layer”. Lamina I (lamina=layer) has been rather mysterious, its fibers are so weird, and it has been largely ignored in favor of Layer II where most C pain fibers (the putative fibers of chronic pain) travel. However, the widespread effect of cells in Rexed Layer one is well known, with studies showing single cells able to sensitize as much as one half of the entire body. Layer I cells are thought to be sensitizers, through some as yet unknown mechanism. They have been called “specialized C fibers” for lack of a better term. These cells are very small in diameter, like C fibers, and lack insulating myelin. Layer I is now going to receive much more attention, thanks to Jeffrey Coull et al.

Since those of us with CP just hurt to death, from touch, from cold air, from sunlight, temperature change, from movement and from just about anything, it is nice to see Coull and his colleagues come up with some confirmation that our nerves are not only hypersensitized, they are HYPERsensitized!!!. More than this, the information should provide a powerful clue to drug companies to finding a way to STOP our burning, and other, pains.

Thank you again to Coull, his colleagues and to Michael Salter at Univ. of Toronto and Yves DeKoninck at Laval University for driving this research. Not only does someone with genius believe us, they are trying to help us. “Praise the Maker”.

For a layman’s explanation of what Coull is saying, see Carole Torsney and Amy MacDermott in the same Dec 15, 2005 issue of Nature. They will let you know how microglia, secreting cells that surround neurons, relate to BDNF release, and what the changes in nerve injury mean for GABA-A and glycine receptors, which can also act as ion channels. If the term “anion” scares you off, Torsney and MacDermott do a very nice job of analyzing the important new findings of Coull and giving a context. Both articles point out that in neuropathic pain, the sensitization can be so great that the patient cannot tolerate the touch of a shirt. While this is hardly the first pronouncement on this topic, it is a welcome repetition of a known fact about severe Central Pain. If it were repeated more frequently, we would receive fewer letters from CP sufferers who keep getting thrown out of pain clinics for inadequate clothing.

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To the doctors who still think central pain is “in our heads”, would you please read a journal occasionally. It won’t kill you. Maybe try getting your Continuing Medical Education credits somewhere other than on a Cruise Ship or asleep among your equally unread colleagues in a boring departmental meeting. Nature and Science are the two leading scientific journals in the world. Science has already published extensive work on Central Pain, including studies from Iadarola which underline the characteristics and severity of Central Pain. It is a sign that “pain” has arrived, when both these journals publish regularly on the topic of basic pain neurochemistry.

Reading them might just, possibly, make you, our doctors, believe us. Either way, we are going to burn. Since you do not have a satisfactory treatment for CP, (according to the NIH) you are still not going to like us, because we do nothing to fulfill your egos; however, if you acknowledge that CP is for real, we will like you better; for you will at least see us as a curiosity instead of as a malingerer. You will STOP doing the routine neurological exam with the safety pin, the cotton pledget, the reflex hammer (Hofman’s sign is better anyway for uppper motor neuron injury–do it by flicking up the middle finger, not by pushing down on the fingernail). Put away the tuning fork; and start using von Frey hairs, occlusive Saran wrap, temperature variation (cold blasts on areas of diminished sensation) and the like, which are actually the way to test for Central Pain. You could also test us with sensory dots for palimpsets and the like, but that is not necessary.

Or, if you favor the simplest method, you could just ask us to put some clothes on the areas that burn. We will even bring our own socks. Test our working memory by telling us to fix a number in our heads and then substract from it in sequence. Compare how much better we do at addition than when we have to fix a number and remember it in order to subtract. Get us excited or upset and watch the burn increase. These are all rational ways to test known aspects of CP as opposed to the routine neurological exam which third year medical students learn.

Babinski’s sign won’t help either. We are not in your office to see which way our toes move. We are there because we burn, we have shooting pains, there are pins and needles sensations, and our muscles hurt. If you just absolutely must have an image, send us where they know how to do functional MRI for pain. You will then have something you can use. You can muse over our cingulum, and the insular cortex and ponder over what we might actually be feeling inside. Are you reluctant to do this because you might be critized by the Managed Care bean counters in the central office. We understand.

In the end, the PhD’s will cure us, but in the meantime, would you please give us the dignity of being real patients. Stop x-raying, surgerizing, medicating, and electroding us until you know what you are looking for; or, have a double blind study which shows your therapy actually benefits Central Pain. Giving us the latest anticonvulsant, hypnotic, or timed release opioid as if it were a “breakthrough” is not particularly candid. Let us know the limits of those three dollar pills at the outset. False hope is overrated and very expensive. You will feel helpless, but that may make you relate to us a little better.

You might as well face it. You are board certified, and that implies you are willing to educate yourself. Dec 15 05 Nature is a good place to start. If you prefer to stay with the NET, we like www.iasp-pain.org/PCU02-3.html from the International Association for the Study of Pain, made up of neurosurgeons and neurologists you can respect, such as those who invented the epidural block, which you probably use all the time. It isn’t such a reach, Central Pain. It just requires an open mind, and oh yes, the willingness to read journals and stop living solely out of your own practice. You don’t want the police to be the only ones who know about DNA, do you?

Here is a quick test. List the function of the following in pain:

1. What is the TRPV-1 receptor and where are C fibers found?
2. How does chloride inhibit action potentials
3. What is the Nav1.3 channel
4. What is the CaV 2.2 channel (bonus points if you know the function of the calcium T channels)
5. What are the functions of NMDA in pain
6. How does disinhibition prevent opioids from benefitting central pain
7. What is the role of MAPK and pERK in pain
8. What is the role of Fatty Acid Amide Hydrolase in pain
9. Which chemicals contribute to the perineural acidosis in central pain and which chemicals increase in the dorsal root ganglion in central pain
10. What is nerve hypersensitization and what is the most severe pain state known to man

If you scored less than 70%, you need a little review.

To those of you doctors who acknowledge that Central Pain hurts, you can forgo the test and simply listen to us. We will teach you best (Sir William Osler’s rule). You don’t need to know that rats with CP chew off their legs in an attempt to get rid of the pain. You can get the story from humans. More efficent and we generally smell better.