Following chemotherapy and other incidents, nerve injury pain in the peripheral nervous system is rather common. Peripheral nerve injury pain has generally improved or ended over time if the severed neuron was able to grow back down the axon sheath and find the area it was intended to supply. This reconnection appears to shut off the pain. The alerted brain has been quieted. Such events are not available in central pain because central injury does not preserve a channel or empty axon sheath into which a regrowing neuron can track. Instead, there are many sprouts and the near end of the injured neuron, each of which is spewing out pain exciters, such exciters playing a dual role in hypersensitization and initiating regrowth.

Wernig et al in Proc Natl Acad Sci U S A
May (2008) have achieved a real breakthrough. They have been able to convert fibroblasts to neurons. These converted cells form into neurons, glia, and even dopaminergic cells. There has always been concern that converted cells might form tumors, but these scientists painstakingly separated the cells turned into neurons from pluripotential cells with fluorescent stains.

Certainly it is gratifying for scientists to finally unmask the transcription factors which will enable the formation of pluripotential cells into neurons. These transcription factors are:
transcription factors Oct4, Sox2, Klf4, and c-Myc

One can only hope the work will reach central nervous system neurons. The wheels of pain research grind slowly, but they grind exceeding fine.

High energy phosphate bonds are the batteries on which the body runs. These high energy phosphates transfer electrons to other chemicals in the body and change them from inert to active.

Reiterating, a kinase is an enzyme which phosphorylates, or links high energy phosphate bonds to chemicals, such as proteins (chains of amino acids greater than 200 in length) to make them active. Peptides, which are chains less than 200 amino acids in links can also be activated by phosphorylation. ATP is not the only phosphorylater but is the most important. Once it is activated by three high energy phosphates, it hands one off and become ADP.

Thus, the prime example of such an energized compound is ATP (adenosine triphosphate), well known as a product of the Krebs (citric acid) cycle which turns out 36 molecules of ATP at every turn, and is at the heart of metabolic activity in the body. We manufacture 45% of our body weight in ATP every day. This shows how important ATP is to metabolism.

One type of receptor on cell surfaces often uses tyrosine kinase, ie. it attaches high energy bonds to tyrosine amino acids. These are called Receptor Tyrosine Kinases, or Ret.

Ret is made of a very large extracellular protein mass, or N terminal region, which is an immunoglobulin. It crosses the cell membrane with a relatively small (about 40 amino acid) domain, and ends at the intracellular portion, the C terminal region, which does the phosphorylating (kinase activity). The Ret tyrosine kinase is termed RTK.

When a nerve growth factor binds to the extracellular N terminal mass, two RTK’s join (dimer). The RTK dimer then has an affinity for phospholipase C and Src proteins. Then certain adaptor proteins link the activation of RTK to signal transduction pathways, such as the MAPKinase pathway signalling cascade.

Ret has its origin in the Runx1 genes (which are part of the Runt gene family). These genes also play a role in differentiation of neuronal (as well as blood forming) cells into sensory neurons, specially pain neurons (nociceptors). In fetal life Runx1 related activity also determines how deeply the sensory neuron will penetrate into the layers of the spinal cord. The more Runx, the deeper it goes. Runx also affects differentiation of sensory neurons in the dorsal root ganglion (DRG), presumably determining which neurons will act as nociceptors and to what degree of sensitization.

One has to wonder if injury to nerves affects the metabolism and activity of Runx1, a facilitator of nociceptor penetration to the deeper dorsal horn. For example, might injury impair access of incoming pain neurons to the deeper layers of the cord. The deeper layers are where descending, inhibitory interneurons synapse as the pain signal crosses to the opposite side of the cord. Might incoming signal in injured nociceptors preferentially shunt to pathways on the same side of the cord? (eg. the superficial Rexed Layer I, or marginal layer), the superficial ascending pathways being predominantly excitatory rather than inhibitory. It is noted that Runx knockout mice do not develop neuropathic pain easily. (Runx knockin therapy is currently under consideration for treatment of leukemic white cells).

Ret is the receptor for glial cell derived neurotrophic factor (GDNF). Before GDNF can activate Ret, it has to bind to a co-receptor glycosylphosphatidylinositol (GFRalpha) to form a complex. This complex hooks two Rets together, which effects the phosphorylation of kinases, such as MAPK. MAPK is a signal transduction pathway.

Here is another area where research in cancer, which enjoys huge funding, may benefit pain research, which has very little funding.

Because Runx1 (one of the Runt genes) and Ret are important in cancer, especially leukemias or other cancers of blood forming cells, the mechanisms of Runx and Ret manipulation are being vigorously studied. When we can manipulate Runx1, we may be able to eliminate neuropathic pain, as seen in Runx1 knockout mice.

We are not dead in the water on pain. We are just charity cases, hoping for a few crumbs to fall from the tables of the masters. Of course, it could just as easily be the other way around, since more is spent on pain than ANY OTHER MEDICAL CONDITION, but cancer is the biggest baddest boy in town, or is it? Which is the greater evil? Is it death, or intractable pain? One is visible and the other is not, but that does not necessarily answer the question. Nature did not give us an organ to feel the pain of OTHERS, but it did give us the means to perceive OUR OWN pain.

There is an ebb and flow as various clinicians and scientists gain consensus or disagree about which neurologic syndromes or symptoms belong in which category. This is not new in neurology, which is notorious for having many terms, defined differently according to context.

One example is the term, “thalamic pain”. Some modern authors reserve this term for post stroke pain. However, the original authors, Dejerine and Roussy, did no such thing. In Tract Optique, they use the term “thalamic pain” interchangeably with the term, “Pain of Central Origin”. Their co-worker Egger did the same, as did S Weir Mitchell in the United States. Splitting pretends a different mechanism which is far from proven. The nature of the pain after stroke is also often identical to spinal cord injury pain. The difference in distribution (stroke pain tends to be on one side of the body) may or may not justify vouchsafing “thalamic pain” to stroke patients; since, really, they are so similar to post SCI pain subjects.

Similarly, it is nearly universal to use the term “spinothalamic tract pain”. However, there are TWO ST tracts, the anterior and the lateral ST tracts, located at quite different places in the cord. It is arguably sloppy to omit WHICH tract one is referring to, yet it is commonplace to speak of both as if they were ONE tract. This is NOT the best medicine can do. Since discrete injury to one or the other tracts is possible, the patient deserves to know the real story. it also helps researchers in neuroantomy to benefit from reports in the clinical literature if the doctor bothers to make a distinction. We learn more that way.

A recent term is actually VERY good. It expresses things well and we are always on the lookout for any verbal help in expressing the dimensions of neuropathic pain.

Spicher et al in Somatosens Mot Res. 2008 Mar;25(1):77-92. have used the term, “static mechanical allodynia”. Although not likely to be spontaneously expressed by a patient, this new term, or “SMA” as they call it is really very good. It comes to us from the world of PERIPHERAL nerve injury pain research, but anyone with central pain knows just what they are talking about.

“Static” is roughly equivalent to Ron Tasker;s “Spontaneous pain”. In medical terms, “static” means as opposed to “phasic”. We don’t really like either of these terms, because they pretend a dichotomy which may or may not really exist.

“Mechanical” just means in response to mechanical stimuli, as opposed to say heat or chemical stimuli. This matters mainly because at the microscopic level different nociceptor neurons are considered “mechanoreceptors” or “chemoreceptors”, divided into low or high threshold, wide or narrow dynamic range, low or high threshold, etc. Wm Willis Jr has shown that some of these neurons can convert to a different type in hypersensitization, so there is more to be learned. It is not always clear that PhD’s mean the same thing as the clinicians when they publish using these terms.

“Allodynia” of course is our old friend, meaning pain from what ought not to be painful. We have already written here that this term also is ambiguous and has also been applied to such things as “location allodynia” which means pain in an area which ought not to be painful, in response to a localized stimulus. (Use search to read more on Allodynia).

So why do we like the term static mechanical allodynia. It is because the authors make clear that it should be thought of as a paradoxical painful hypo-aesthesia. This is really good. The authors came upon this by discovering that vibration of a painful area caused that area to lose some sensation. They were able to outline which branch of a given nerve was injured by observing which area became less capable of sensing, ie. which area became hypo-aesthetic.

What we like is that the authors have no problem whatsoever using the term “Painful Hypoasthesia”. This sounds like an oxymoron, and that is exactly why it is good. It helps us to express what we have been saying for so long. Yes, it is numb there, but it really hurts.

Spicher even goes so far as to say regarding paradoxically painful hypoesthesia, “the mechanism of pain sensitization is probably central and referred peripherally to the skin by a painful hypoaesthesia.” Read as it is worded, this analysis is really almost humorous, yet it is quite rational.

This statement is a face on the doctors who call central pain patients crazy. They will have to include the authors in their denunciation if they persist in their stubborn refusal to understand that nerves may be too injured to transmit normal touch, but more than adequate as a conduit for really severe pain.

It is interesting that vibration dulls the pain of peripheral nerve injury. We hope more will be done to study this in central pain.

While fMRI looks at 3D spatial imaging, PNMS looks at activity at the cellular level. It has been a traditional tool for chemists. Now it is expanding into medicine and seems highly likely to become of considerable research and clinical use.

Schizophrenics, for example, have been shown to have reduced N-acetyl aspartate in the brain. You will recall that the two excitatory amino acids are glutamate and aspartate.

N acetyl aspartate (NAA) gives off the highest signal in Nuclear Magnetic Resonance Spectroscopy of any substance in the brain. NAA is also decreased in other conditions such as Alzheimer’s and stroke. The reported findings therefore are non specific. In the brain, NAA comes from from aspartate and Acetyl CoA.

Acetyl CoA is involved in energy production and fatty acid reactions; and indeed, we find NAA involved in formation of myelin in glial cells (neuronal).

Pain patients have to worry about N-methyl-D aspartate (NMDA), a pain chemical. An acetyl group and a methyl group are not far apart, Acetyl, a functional group in organic chemistry, refers to a Carbon atom double bonded to an Oxgyen atom, and singly bonded to a methyl group. (R-C=O) Despite the fact that a minor alteration in NAA concentration is linked to the major disorder known as schizophrenia, too many clinicians do not seem to realize that increased NMDA wreaks havoc in the pain system. Few pain experts, if any, would deny this, however. NMDA is very important in sustained neuropathic pain.

Strangely, no one has used PNMS to study central pain, nor any other pain for that matter; but it has now been used to study pain in fibromyalgia. The scientists Bustillo et al in Arthritis Rheum. 2008 Feb 29;58(3):903-907 showed that using PNMS revealed that glutamate levels in the insula are a good indicator of fibromyalgia pain.

Elsewhere at this site, Crick and McHenry reported that the “painfulness of pain” was located in the insula,(a new principle when the authors first collaborated, but an established concept now).

Here is evidence that insular glutamate is a flag that fibromyalgia patients are having pain. Surely investigators will not look past central pain forever. We have long needed a marker, an objective tool, to help establish the reality of central pain.

Bredeloux et al in J Med Chem. 2008 Mar 6 report that an analogue of neurotensin; namely c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012) penetrates the blood brain barrier and causes profound analgesia. This drug can be administered peripherally, unlike Prialt (ziconotide), which is given into the spinal fluid. It is somewhat unexpected given that neurotensin injected into the hypothalamic paraventtricular nucleus does not affect pain threshold.(see Yang et al Neuropeptides Jun 07); whereas arginine vasopressin injected into the PVN DOES cause antinociception.

However Roussy has shown that neurotension I injected into the spine and supraspinally does cause antinociception, so we must set the PVN aside for now, concluding that different mechanisms are at work in the ventricles to compared to the surrounding area. J. Neurochemi Jan 22 2008).

Ventricles are spaces in the brain, in which cerebrospinal fluid circulates. Dobner in Peptides Oct 2006 DID show marked antinociception from NT into the periAQUEDUCTAL grey. The cerebral aqueduct is a small canal in the midbrain measuring about 3/4 inch, which connects the third and fourth ventricles.

In 2006 Bredeloux showed (Behav Brain Res Dec) that injecting neurotensin INTO the ventricles had fairly potent pain suppression, which these researchers concluded was linked to the opioid system. There is also evidence that neurotensin II can do the same thing. (See also Sarrett J Neurosci Sept 2005)

It is not an absolute breakthrough since the competitive neurotensin compound also causes severe hypothermia. It is touchy trying to stop nerve activity without having undesiable side effects. Still, most cells have unique receptors, and it is usually only a matter of tiem before a drug can be idnetified which blocks one receptor without blocking another.

Tuysuz, et al have reported in Neurogenetics. 2008 Mar 6, that congenital insensitivity to pain can be seen in those who lack the gene for neurotrophic tyrosine kinase receptor type I. This receptor is activated by nerve growth factor. The trait is recessive, which means both parents must have one of the genes to give two doses to offspring.

There are posts elsewhere at painonline which discuss the fact that tyrosine kinase B (TrkB)is a specific for neurons which transmit pain. Presently, there are no drugs to suppress either tyrosine kinase B in specific, nor tyrosine kinase receptors in general.

Because tyrosine kinase receptors are valuable in powering nerves to sweat glands and in certain other neurologic roles, a general blocker of either Trk or the receptor would not be helpful. Rather, we need specificity. A good comparison would be drugs which block the beta2 adrenergic receptor, rather than block beta 1 as well.

We have spoken before about the importance of energy supply in the body in determining the progress of chemical reactions. Energy is supplied by kinases and taken away by phosphatases. The kinases which energize pain cascade pathways need intense study to stop the nightmarish sensations of central pain.

Whether it is real or imagined, there seems to have been a lull in pain articles that shake things up. Not to despair, the pauses usually indicate someone is working out something new and important.

One area receiving attention is opioid hypersensitivity. It is being reported mainly in patients with uncontrolled cancer pain, where rapidly increasing opioids may cause a sudden increase in pain. Some authors recommend opioid switching to a different medicine in lower dose. There is no solid data yet on the effectiveness of this method. Once the hypersensitization is noted, there are also reports of successful detoxification under general anesthesia, but the patient is then expected to go on WITHOUT opioids.

Next, we have written much on the TRPV1 channel. Recently, another transient receptor potential channel has received attention, the TRPA1 channel. It was initially reported to the be the channel modulating noxious cold response (exaggerated cold response is a common feature of central pain), but another study in knockout rats* failed to confirm that TRPA is necessary for initial sensing of noxious cold. We will await more word, since these kinds of things generally sort out into something concrete that makes sense.

Andrade et al in Neuroscience. 2008 Jan 9 have noted that allyl isothiocyanate seems to do for TRPA what capsaicin does for TRPV1. Interestingly, ruthenium red blocks BOTH channels. Additionally, TRPV1 fibers which are sensitive to capsaicin are also the ones which carry TRPA1 which can be activated (agonized) by allyl isothiocyanate.

The expanding knowledge of ion channels has created a new branch of medical illness, known as “channelopathies”. The transient receptor potential channels are comprised of 28 known channels permeable to monovalent [single charge] cations [the charge is positive], which are divided into several groups. TRPV channels are among those permeable to divalent calcium ions [Ca2+]. Such channels are the ones concerned with pain. TRPV stands for TRPvanilloid, which is thought to be the primary channel afflicting central pain patients, at least as to dyesthetic burning. Since cold allodynia is so common in central pain, we might have to make room for another tormentor, TRPA1.

The method is being developed of blocking these channels by intrathecal injection of antisense oligodeoxynucleotides, which are counterfeit bits of DNA-like material which gum up the works of a channel. Selective blockade of the TRPV1 channel can be achieved by SB 366791, while TRPA is selctively blocked by the antisense oligonucleotides. Significantly, both TRPV1 activity and TRPA1 activity are blocked by the selective neurokinin 1 receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbony-1-l-prolyl]-N-methyl-N-phenylmethyl-3-2-(2-naphtyl)-l-alaninamide.

Studies indicate that after TRPA1 activation with allyl isothiocyanate, mast cells release histamine, which involves tachykinins, such as bradykinin.These steps are part of classic neurinflammation. Sympathetic blockade with guanethidine did NOT stop the pain (nociception) from channel activation. A fair number of patients with central pain after spinal cord injury also display sympathetically mediated pain. Such patients are sometimes identifiable clinially by developing thinned shiny skin at the ends of their extremities (eg feet) and loss of hair there, or by response to IV sympathetic blockade. Time should demonstrate whether a dual therapeutic approach is indicated in these people, one for the TRP channels and one to block sympathetically maintained pain.

Yang, et al in J Pharmacol Sci. 2008 Feb 9 have developed a method of isolating the omental fat apron of the gut in anesthetized rats which exploits the reflex hypertensive response to pain agents. This approach may yield better ways to suppress bradykinin participation in inflammation. Already the use of the reflex hypertensive response has allowed the determination of whether one agent is acting peripherally or centrally. The technique compares application of an agent topically to the exposed omentum and then giving it intravenously or intrathecally.

The authors state, “Topical administration of a non-acidic analgesic, mepirizole, inhibited the RHR by topical BK [bradykinin[ by only 20%, but intravenous mepirizole inhibited topical BK by 96.2%, indicating its major CENTRAL action” Central pain patients are frequently left alone in skepticism as to their pain. The bradykinin test may provide another avenue for identifying real pain of at least one variety. Admittedly, the neuroinflammation is going on at a cryptic level, inside the brain or cord, so gut fat may not help us establish what we want to establish, namely, the reality of central pain.

On another topic, scientists in Iran have reported that extract from leaves of Danae racemosa relieve pain when they have a high content of quercetin and kaempferol.

Additionally, Wydenkeller has reported a new method of using ordinary contact heat points to measure evoked potentials, but this is not clinical yet. Laser has long been used, without really pinning down who has neuropathic pain, so it is unknown whether this is a breakthrough or a mere simplification of existing study method.
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*A knockout rat is one in which the gene producing a given protein structure has been disabled. Knocking out a gene allows us to determine the function of the gene, as well as study the results of failure of the protein that gene produces. The technique is powerful and the inventor, Mario Capecchi at the Univ. of Utah, won the Nobel prize in Medicine last year.

Note: Because this article addresses one of the questions spinal cord injured people ask about gender identity, it is not for the squeamish, and somewhat graphic medically, so it is not recommended reading for children.

Painonline contains many articles regarding the loss of identity which is experienced in severe central pain. It is more or less axiomatic that self identity is not just a frame of reference, it is something fundamental to the human experience.

It does not take much imagination to realize that if one finds oneself thinking completely new thoughts, having completely new priorities, and attaching totally different significance to various life experiences, there is a troubling question of who the person is.

Fundamental change is considered salutory in the religious context. The putative change is sufficiently profound in some circles to have drawn such terms as being “born again”.

How about in the pain context? In a different sense, “born again” seems potentially valid here as well, although many central pain sufferers might choose something different, such as “deborned” or even “destroyed”. If the impact is the reverse of becoming a new and improved individual, most would put it more in terms of a burned out hulk. What is left is not so much an altered perspective, permitting heightened insight, as it is the ultimate distraction. Pain is just so powerful. It is an open question whether the person who has “got religion” is, in the mortal sense, more fundamentally changed than the person who is immersed in severe, unending physical pain.

We grant that adversity has its uses and are minded of Maxwell’s caution against hasty guessing in the “algebra of adversity” and devaluation of “the sandpaper of circumstance”. The question is whether the shaping that is going on is refining or disintegrating. Sometimes it is very difficult to tell.

Coping with central pain requires such estensive and all encompassing alterations that the field can hardly be addressed. One relates to inner drive and ambition differently when the number one priority is to avoid evoking the burning dysesthesia. In fact, the preoccupation is so great, it is hard to come up with what might be number two. Perhaps number two begins at what would be number one in ordinary people. Or perhaps, more frighteningly, the priorities and perceptions of ordinary living become distant memories, of diminishing significance, except for times when events converge to ease the dysesthesia.

No one realizes more the alteration in identity than the central pain subject. It is as if one has a fascination with the rudiments of survival. In a big broad world, it is as if one cannot take ones eyes off a particular object and the great deal of other is discarded out of mind as unavailable.

How does it feel to recognize oneself as fundamentally altered. If an arm is missing, major accomodations and adaptations must occur. None of them is pleasant. However, when the identity is gone, the bewilderment, disorientation, and confusion is almost overwhelming. It is difficult to maintain a values system in such a condition. It is admirable how many central pain patients are able to reconstruct some sort of social order despite the pain, but there is an element of the pathetic. One can go through the MOTIONS without experiencing the EMOTIONS which guide and modulate experience.

Consider for example, a hypothetical spinal cord injured person who through various means can still experience ejaculation, but cannot feel pleasurable sensation. Let us add the further variable to our hypothetical that the person with dysesthesia cannot experience physical pleasure from any touch whatsoever, not just sexual touch. Has this person nevertheless had sex by virtue of ejaculation? It is a matter of semantics. It is certainly not the sex your mother didn’t tell you about. Real sex has a reward. Without it, human life on earth would cease. Sex is not a human misfortune. Lack of capacity for it is a human misfortune. If childbearing is not the object, does sensationless ejaculation have a reward? If so, what is it?

Emotionally, whatever sex conveys has been fundamentally altered. Of course,the person can decide to attempt to get around the loss of the emotional comfort of physical pleasure, to forgo what touch provides, and attempt to use visual, gustatory, or auditory stimuli for pleasure, but how good are these substitutes? Would any human being forego the pleasure of touch in order to hear beautiful music? It is beyond a Hobson’s choice. It is about identity. And of course, central pain is not an absence of touch, it is the substitution of burning for it.

Even a cursory consideration would lead to the conclusion that such a person needs support from other areas, such as praise, social recognition, friendship, and intellectual stimulation. However, pain exacts a heavy tax on all these modalities of life reinforcment. A quantitative evaluation of what therapy might be required to actually help someone in deep pain live a semi-normal life goes to some things which seem almost absurd on the surface. For example, should the public transportation systems provide free passes to museums, to theaters, to the seashore, to anywhere that the pain can be diminished or perhaps even forgotten for a time? What health plan would pay for this?

Surely the public would revolt at having its tax money so allocated, yet such matters are presently the only remedy available for the merciless burning which must be endured. Without elaborate support, a central pain person shrinks. MRI shows that even the brain volume shrinks as the erosion of self is worked by constant pain.

Recently, some psychiatrists at Duke took a look at the issue of pain as a central event in life. See Perri and Keefe, Journal Pain, December 2007. These authors gave questionnaires to 47 patients about the “experience of persistent pain”. This article is extremely well worded, as the authors indicated they were interested in how persistent pain “serves as a turning point in the individual’s life, forms a reference point for personal identity, and affects the attribution of meaning to other life experiences”. These are the BIG THREE psychological parameters which characterize the “pain astonishment” which blasts away at the meaning of life as the pain becomes mortally eternal, ie. pain as a turning point, identity, and the meaning attributed to life experiences.

It is not too surprising, and in fact, inevitable, that after studying these patients, Perri and Keefe concluded that “The experience of persistent pain can serve as a major turning point in patients’ lives, affect patients’ interpretations of other life events, and become a key component of patients’ identities.”

If a doctor has seen ten cases of bona fide lupus, the odds that she will diagnose lupus in patient number eleven are very high, higher than it would normally be. This impact of experiental effect is called heuristics. It is the tendency of ongoing repeated happenings to shape our perception of reality and likelihood. Since pain is ongoing, it is not reaching to say that if pain has ruined the last ten years of one’s life, it is not surprising for the pain patient to face the next one minute of life with lowered expectations for happiness. This is in every sense an heuristic pehnomenon. With central pain, the fears prove to be well founded, and thus the heurism increases to a point where something has to give.

There has to be some foundation mental perspective from which to face the certain and neverending tragedy while still giving life meaning. For most central pain patients, this means avoiding stress of any kind. Someone said, “It gets easier when you stop expecting to win.” Conservation of energy becomes essential. Still, it is frightening to watch human life and loved ones float past as the CP patient hangs on and measures their efforts toward others as feeble and mostly ineffectual. In other words, the social and psychological effects of central pain are massive.

Perri and Keefe have adopted a new term, “centrality of event”. It is a very useful term and we like it. It is true that “heuristics” also describes such matters, but few people are familiar with the term. Creation of a new phrase, “centrality of event” may serve to remind the public and professionals of what Augustine said many centuries ago, “Physical pain is the greatest evil.” Those who have been unmade and undone by pain salute the psychiatrists who are studying what they ought to be studying, the magnitude of necessary coping, rather than simply making standoffish and unhelpful comments about pain being the result of mental weakness. As we have said before, such ideas never get past the capsaicin injection challenge. Still, it is nice to see psychiatrists recognizing the centrality of the event of persistent pain. We thank them for the vocabulary and for their enlightening perspective.

Now, how about that ride to the museum? No? Well, at least the sky, the mountains, and the ocean may still be available. The act of experiencing them will not be considered justifiable therapy by others, and certainly will not be seen for what it really is, a means of survival.

We assure Perri and Keefe that central pain is a central event.

The Golden Rule:

Administer analgesia unto others as you would have it administered unto yourself.

This article can be read without a knowledge of brain anatomy, but reference to a diagram helps pull it together.

A simplified chart of brain anatomy can be viewed at
http://farm1.static.flickr.com/59/157243309_b4cf481918.jpg
Save image and then enlarge the jpeg image to read the legend.

Pain travels up a peripheral nerve to the dorsal root ganglion, enters the cord via the dorsal horn, crosses over, ascends to the thalamus inside the brain, and then on to the primary somatosensory cortex, (SI) on the brain surface. Right? Apparently, Wrong. The SI does not increase cerebral blood flow (which is thought to reflect brain activity) as the thalamus does, when the thalamus responds to cutaneous pain.

Further, we should have been suspicious after the reports of BILATERAL central pain following UNILATERAL lesions in the brain.(See Canavero S, Bonicalzi V Bilateral Central Pain with Unilateral Brain Lesion Eur. Neurol 1999:42:118, See also Kim, J.S. Delayed-onset ipsilateral sensory symptoms in patients with central poststroke pain. Eur Neurol 1998:40:201-206) With all the focus on what was going up toward the brain (orthodromic), there should have been more attention paid to what was coming down (antidromic). In other words, there was a circuit going that traveled BOTH directions. The PET scans are going to have to look at what is going downward in central pain, not just what is coming upward into the brain. Thalamic circuits are not a new idea, just not a popular thing to study.

Cortico-cortico, and cortico-thalamic crosstalk should have been recognized and further investigated before we set up imaging experiments to confirm old ideas that were sure to be disproved.

So far, every attempt to simplify pain has only succeeded in revealing greater complexity. It is something like Gordon Moore (of Intel) who proposed a law that the number of transistors which could be placed on an integrated chip would double every two years (Moore’s “law”). By analogy, the known complexity of pain circuity/chemistry will double every two years (Painonline’s law).

It is clear we must find a cure before threading out every truth. Perhaps someone will find a way to deliver resiniferatoxin to EACH dorsal root gangion to kill all the TRPV1 receptors. Then we can search out the chemistry at our leisure. At the present time, however, theory is so fascinating and so fluid that few have decided to go for the kill. (See below for one possibility from Sergio Canavero).

How primitive are we in our understanding pain anatomy? Well, we don’t really know. We don’t know what we don’t know. If we did know the truth, then and only then, would we know how close or how far from the real truth our science is.

Certain of the fMRI and PET findings are so much in conflict that some have even termed such research “modern day phrenology”, which is hopefully an unjustified assessment. In the opinion of the painonline editorial staff, the researchers are missing the obvious weak point, STUDY DESIGN. We need to get clinicians closer to the magnet and imaging scientists closer to the clinicians. A patient who evokes nerve injury pain to a particular stimulus will disappoint if a different stimulus, or none, is being applied. Knowledge of CP fundamentals should make this obvious.

There is plenty of emotion which modifies brain response to any pain. When researchers understand more about the confounding nature of mental status during pain testing, then they should be able to design better investigations.

For example, many SCI patients have some degree of spasticity. The loud clacking of the MRI magnet startles and annoys them, and this can be distressing. Perhaps the central pain subject is having a terrible time holding still or is about to choke on saliva. Perhaps the cold of the room is burning their skin (dysesthesia).

The brain response to such peripheral matters may have nothing to do with pain, but would almost certainly show up in the study. Using concommittant EEG as a backup is an interesting proposition, but does not eliminate problems stemming from poor study design.

Another example might be the person already in serious spontaneous pain from CP. This person may well respond to an evoking stimulus, but where is the imaging lab prepared to apply various evoking stimuli, such as implements of graded sharpness, temperature probes, occlusive skin covering, etc. ?

A PAIN IMAGING CENTER, set up at say the NIH would be best, where study design could be refined, but there is no money at the present time. There may never be unless the nation finally decides that pain is a priority, similar to the way infectious diseases are considered a priority.

Since more money is spent on pain than any other medical item, it seems reasonable to take pain seriously. However, we tend to take only our own physical pain seriously, not that of others, and not as a general matter for study. Yes, in the future, this attitude will seem to have been Medieval, but this is the climate in which we live.

Under this fiction, which excludes oneself, pain is there and there is not much you can do about it–stop whining. As we all know, “There is no problem which cannot be made worse by whining about it” Severe physical pain should be excluded from this axiom. We suggest a new saying, “There is no axiom about pain so insensitive that it cannot be made worse by implying that those in severe pain are whiners.”

It is conspicuous how silent the “stop whining” crowd become when they personally are laid out on the surgical table for an operative procedure, where pain relief is suddenly, without any discussion at all, a HUMAN RIGHT of the very FIRST order. Period. End of report!

Of course, with cost containment now an issue, maybe they would like to have a less expensive, but certified, personal pain trainer come into the surgical suite and mock them by shouting “stop whining”, in place of their costly anesthesia. Even childbirth today rates an expensive epidural, and we have been assured by parturient central pain sufferers that central pain is much worse than labor pains.

There are those who assume nerve injury pain could not be very severe, but this misinformation can be eliminated easily with a tiny injection of capsaicin, to turn on the TRPV1 receptors in one small area. Then, the magnitude of the identical sensation over a large area of the body becomes, well, inconceivable. There are no skeptics about nerve injury pain among capsaicin testees, yet the burn from capsaicin is modest compared to the real thing, to fully elaborated central pain, the worst pain state known to man. It is also certainly the most relentless.

Given the misunderstandings about the multiplicity of pains, and variance in evoking stimuli in nerve injury, it should therefore come as no surprise that pain imaging studies frequently fail to agree with each other. Study design cannot progress without the inclusion of an expert clinician to weigh the variables in the pain calculus. Since fMRI scientists typically regard the magnet as proprietary to the specialty, they are led into frequent errors in recognizing the different types of pain.

Svensson et al in J Neurophysiol. 1997 Jul;78(1):450-60, shed early light on how the brain handles pain. The researchers used a technique of nuclear medicine known as positron emission tomography or PET. What is looked for is regional cerebral blood flow. This is taken to indicate a reaction or area of processing which reflects brain activity. One must be careful to sort out the emotional reaction centers since these can be expected to be involved in any pain experience.

For quite some time it has been unclear whether emotion and pain can really be separated, but fMRI and PET seem to indicate that they are separable. This information, if correct, undercuts many assumptions about pain from certain behaviorial theorists, who prefer to see all pain as emotional in origin (although it escapes us what could possibly be emotional about holding one’s hand over a Bunsen burner).

There has long been talk of the “painless soldier”, and such, to the point where some practically stopped acknowledging that pain was an actual sensory phenomenon. Pain seems to be more like water flowing, which can be stopped by a dam (distraction) but if continuing, soon overflows the barrier. Anesthesia just happens to be a very high barrier. The pain is blocked, but when the patient awakens, the cutting has stopped, so pain is much less. Yet, pain messages in the brain can be recorded even as the patient is anesthetized.

And, reexamination of the painless soldier usually reveals that once the shock is past they may require large amounts of opiates, even if the bullet has long since passed through. Further, for every soldier who felt no pain, there are thousands who felt plenty of pain. What is happening is that once there has been time for neuroinflammation, for the glia which surround neurons to put out the growth factors which activate the inflammatory chemicals so that the area will be hypersensitized, and therefore not used, the pain has grown exponentially.

The number of glia increases by four, but the pain seems like it has grown to the fourth power. New ion channels, not seen since fetal life, come pouring out of the protein factories in the DNA/RNA. Acids form, and the TRPV1 channels open like floodgates to allow pain currents to pour in. THIS soldier needs morphine, and plenty of it. Once healing occurs, the neuroinflammation, because it is under proper control, subsides, and the body allows the soldier to be up and around.

However, for the poor unfortunate who progresses to permanent nerve injury pain, there will be no relief, the pain will never stop. Eventually, the soldier is not a soldier any more, and in many ways, not human. They cannot whine, they can only giggle nervously as they dangle helplessly between earth and hell. If they are paralyzed, others may defer to the injury; but they never defer to the pain, because everyone EXCEPT the CP sufferer knows that nothing is worse than paralysis.

The deeper truth is that there is something much, much worse, endless severe pain. “Will someone please make them stop whining?”. Yes, right after we get the paralytics up and running around the track, we will be sure to tell them to shut up in the name of decency. Let us summon those who successfully use shaming in the operating room to silence the cries. Hmmm. Where are such people when we need them??? There seems to be a shortage at the moment.

Then, perhaps we might call for pain clerics, instead, to read surgical patients the book of Job. What! no ecclesiastical anesthesia in the operating room either? Then, perhaps we will be compelled to do the hard work of nerve biochemistry, since we cannot keep central pain subjects asleep for the remainder of their lives. A shortcut would save a lot of trouble, but it looks like this problem will require man to follow the “out of Eden” command to subdue the earth.

This really tests your faith, sort of like other theological issues such as mosquitos, Antarctic winters, the impact after falling off the Empire State building, and the jaw muscles of crocodiles. By the way, why doesn’t God deliver turkeys already plucked and roasted to set on the doorstep?–Wait! Please excuse. That sounded a little like whining. It is hard to delineate unjustifiable whining. It depends on whose ox gets gored. (We attempt a little humor here, in respect to Dr. Patrick Wall’s plea not to theologize pain illness, for fear this would lessen the drive for scientific research.)

During WWII, forty times as many of Merck’s 1/4 grain syrettes of morphine were used as there were soldiers in the military, wounded or not. What a lamentable failure of proper pain prevention. Foolishly ignorant of the emotional ways to block out pain, the military included the syrettes in every parachute and in every kit, along with a tourniquet and some sulfa. (see Flags of our Fathers, by James Bradley). A manual on how to psychologically overcome pain would, if you subscribe to some opinions, have been unbreakable, cheaper, and equally effective. May such authors have a bundle of these instructional pain avoidance booklets to bury themselves in during the next root canal, gasoline explosion, or nearby asteroid collision.

Henderson et al in Neuroimage. 2007 Nov 12 presume a “pain neuromatrix” (a theoretical term, not necessarily anatomically correct), by which is meant the ANTERIOR-cingular, insular, somatosensory, and cerebellar cortices; as well as, emotional pain processing areas, which they indicated includes MID-cingulate cortex, dorsolateral prefrontal cortex, hippocampus and cerebellar cortex. Unfortunately Henderson had no way to show whether activity (rCBF) in the named areas was excitatory or inhibitory. At least in the case of the roof structures in the cerebellum (vermis) we know, thanks to Carl Saab, that the action is inhibitory, so it may be presumptive to automatically assign cerebellar pain tracts to the emotional column.

Cerebellar response to central pain was first reported at the Ninth World Congress of the IASP by Carl Saab, who has authored articles here at painonline. His findings were considered so radically different from existing theory, that a storm of objection met him from some individuals. He has been vindicated many times over.

Svensson’s study is a bit more intriguing because it addresses the bilaterality of pain centers to a greater degree. We list below the findings. Remember that pain coming up from the body is CROSSED at the cord and so pain on the right side usually shows up in the left brain. Crossed pain is contralateral. Pain coming up and staying on the same side is ipsilateral (such as in the outermost marginal layer, or Rexed Layer I of the dorsal horn of the cord) With this in mind, one can see that most pain shows up on the opposite side of the brain.

Svensson found regional Cerebral Blood Flow after pain in:

Contralateral anterior insula
Contralateral somatosensory cortex (SII)
inferior parietal lobule (Brodmann area 40)
contralateral lateral prefrontal cortex (Brodmann areas 10/46)
contralateral anterior cingulate cortex

ipsilateral premotor cortex (Brodmann areas 4/6)
Ipsilateral cerebellum.

Astoundingly, the primary somatosensory cortex (SI*) {traditionally considered the main pain area] and the primary motor cortex (MI)[considered of late to be a primary pain area] lit up a little but the difference of pain/nonpain was not statistically significant.

Svensson noted a NEGATIVE correlation between changes in rCBF for thalamus and MI/SI for cutaneous pain. This means that what causes increasing blood flow to thalamus (presumably pain) causes a DECREASED activity in BOTH the primary sensory and primary motor areas. This raises the question whether SI and MI might actually be trying to shut down when the thalamus is overloaded with pain. Given reports of pain benefit from transcranial DC current to the primary motor cortex, SI and MI may actually be acting as pain supressants at a certain point in the pain curve. In other words, exactly the opposite of what they have long been assumed to have been doing, “causing” or “generating” the pain.

Svensson also noted a POSITIVE correlation between blood flow to the thalamus and the anterior insula. This nearly cements the claims by Crick and McHenry of the important place of the insula in pain traversing the thalamus.

More studies are needed, but it looks like we must go back to the drawing board. So many assumptions are in question that we must go back and question everything carefully.

Major assumptions about whether a patient is in pain (eg. if your SI doesn’t light up, you are not in pain) have followed PET and fMRI, but of course it is necessary to actually know where pain TRULY appears before such value judgment should even be attempted. As the studies above show, such hasty conclusions were unjustified, since SI does NOT light up when the thalamus does.

Central Pain is also known as thalamuc pain, although of late, some have used thalamic pain to refer to central pain after stroke. There is no absolute requirement to so limit the term “thalamic pain” since Dejerine and Roussy used “thalamic pain” and “pain of central origin” interchangeably. S. Weir Mitchell also termed it pain of central origin. Riddoch first popularized the shorter term “Central Pain”.

Some now wish to call it Central Pain Syndrome, but the addition of “syndrome” while applicable, stems from the variation seen in discrete etiologies, not merely from a collection of identifiable clinical signs. Dr. Canavero chooses “Central Pain Syndrome” and that is good enough for us. He and he alone has done a good job of describing how the condition differs in say, SCI vs. stroke, traumatic brain injury vs. MS, etc. To our knowledge, no one else has produced such data, although it is essential to grasping the problem.

Canavero reminds us that central pain manifests differently according to the etiology, and quite possibly according to the anatomical location. We like anatomy, it is so much easier to grasp than chemoarchitecture. If you have not yet purchased a copy of Sergio Canavero’s book from Cambridge Press, “Central Pain Syndrome”, you should certainly consider doing so.

Clinical signs also have their drawbacks. Ultimately, how we should subdivide the pain may well turn out to be based on acidity levels or components of neuroinflammation, rather than by clinical signs, which are elusive for any but the most experienced and highly trained expert, and sometimes, even for them. The reason is the lack of a vernacular for Central Pain. Without a vocabulary available, the patient can only go so far and no further.

The clinical picture is probably more reliable now than any imaging–ie. a careful medical history and skilled exam, following the guidelines of Dejerine, Egger, and Roussy on history and exam in pain of central origin (including testing for Mitchell’s delay).

It seems a bit ironic that before Dr. Francis Crick and Dr. Kenneth McHenry linked the “painfulness of pain” (Crick’s term) to the insula, in a short article at painonline; (shortly thereafter Crick alone published the complete article in the journal Pain), pain professionals paid little attention to the insula. Yet, presently, after only a year or two, the insula is considered the lead area in pain.

The imaging teams are doing pain patients a great service and it seems likely that it will shortly be impossible to challenge someone with severe central pain, because imaging will have taken it out of the realm of doubt. It is not really in doubt now, for good professionals, but too many ignore the literature of the past, where the characteristics clinically of central pain were well worked out. The signal quality of burning dysesthesia, which is that it evokes with LIGHT TOUCH, but NOT heavy pressure or hard blows, is hardly even mentioned in the literature today.

Other important features of CP such as Mitchell’s Delay and atopoesthesia are almost unknown. The imaging scientists will overrun the examiners before they make themselves learn the lessons of the past. Then, the position of CP will be secure. This is not the goal of course. A cure is the desired end, but just proving that CP is lurking should lead to much more intense study.

___________________________________________________
*The “I” in SI is a Roman numeral.

The clinical signs of central pain can be reviewed at the various articles here at this website or by obtaining a copy from the IASP of Pain, Clinical Updates, “Lessons from my Central Pain” Volume X, No. 3 Sept 2002. Requests should go to:

IASP
909 NE 43rd St. Suite 306
Seattle Washington
98105-6020
USA
Tel: 206-547-1703

Other excellent publications on pain are available through IASP.

Certain Brazilian natives have used extract of a plant related to Junipers, known scientifically as Humirianthera ampla Miers, for the treatment of the pain and swelling of snake bites.

Humirianthera amplis is already known for its production of humirianthol, acrenol, and annonalide. Clicking on the map at http://www.discoverlife.org/mp/20m?kind=Icacinaceae
illustrates the global zone at which these plants grow. Brazil features as the leading area. A photo of the plant can be found at http://fm1.fieldmuseum.org/vrrc/?page=view&id=26340 (note, it is the roots, however, which are used for antinociception).

Humirianthera is one of the Icacinacaeae, and the active chemicals are considered to be di and tri terpenoids, which are also known as isoprenoids, because they are derived from five carbon isoprene units. In chemistry, the suffix, “oid” means “similar to”. The groupings are chemically similar to isoprene groupings.

The interesting thing is that these compounds are LIPIDS. Lipids are naturally occurring fat soluble molecules. Properly, fats are triglycerides or similar compounds. Triglycerides are usually three fatty acids linked to a glycerol. Glycerol (C3H8O3) is a triatomic alcohol, and an alcohol has one or more hydroxyl (OH) groups attached to a carbon (C) atom, in such a fashion as to replace what would typically be hydrogen (H). Fatty acids usually have even numbers of carbon atoms and generally follow the formula CnH2n+1COOH. The COOH group at the end, attached to the lipid, is known as carboxylic acid (COOH).

Coincidentally, fatty acids are one of the substances most responsible for the images generated in MRI. So it is no wonder that the brain and spinal cord light up so well in MRI–nervous tissue is full of fatty acids.

As you know, the local acidity leading to nerve injury pain has been linked at painonline to fatty acid amide hydrolase (FAAH) abnormalities and the downstream formation of fatty acids from altered lipid metabolism in nerve injury pain and neuroinflammation.

Painonline has consistently attempted to detail the cascade of lipid derived acid structures, primarily because those with burning dysesthesia consistently describe nerve injury pain as “like acid under my skin” which in actuality, it is. We desire the medical profession to accept such symptoms as normal expressions of an abnormal situation, not the invention of fevered minds. Fortunately, the science has come our way in recent years, and few question that the acidity is a real sensory phenomenon.

We have spoken in terms of actual acidity to try to avoid the stigma of calling nerve injury pain “bizarre” burning. Use of the term “bizarre”, when simple “chemical burn” would do, makes it seem unreal and not worthy of treatment. It is true dysesthesia MIXES sensations, but only in that sense is it bizarre. “Novel” or “unfamiliar” are better terms. The creepy, sick aspect of the burning is also real, but simply sitting hard on the tailbone or being struck in the gonads can cause “sickening” pain, and these pains are not dismissed as “bizarre”. It is too easy for the uneducated to decide that bizarre pain is something had by bizarre people. This would be like saying when we create animal models of central pain that we are making the little rats “bizarre” rather than giving them a pain state.

The terpenoids (isoprenoids), common in plants, are a very large class of chemicals and are often aromatic. Interestingly this feature is demonstrated in the eucalyptus, and in the aromatic flavor of cinnamon, ginger, and cloves. Also interesting is the fact that the cannabinoids in the Cannabis plant are terpenoids, and are also aromatic. It is not known if cannabis benefits nerve injury pain.

Passing on the addictive potential, which is always a concern, cannabinoids are not generally regarded as potent against Central Pain, but research continues. Nevertheless, cannabinoids, which are vanilloids, do have activity at the Vanilloid-1 receptor (aka TRPV1), which is also the capsaicin receptor, which is capable of reproducing PART of the dysesthetic burning of Central Pain.

Gunthrope et al in March 38 2007 Journal of Pharmacology And Experimental Therapeutics DOI: 10.1124/jpet.106.116657, reported on a new drug, SB-705498. This drug is now in clinical trials. Signficantly, it blocks opening of the TRPV1 channel in response to capsaicin, heat, and ACIDITY as low as pH 5.3, which is more acid than is thought usually to occur in central pain. The binding/blockade is rapid and reversible.

By comparison, resiniferatoxin blocks TRPV1 permanently.

Johnson and Johnson are studying another TRPV1 blocker, JNJ17203212, to prevent cough. See Battacharya J Pharm Exp Ther Aug 9, 2007.

Gavva et al at Amgen have reported that two more TRPV 1 blockers, AMG 517 and AMG8163, also act against heat, acid, and capsaicin pain. Amgen has already contributed articles to painonline.

Luiz, et al, reporting in J Ethnopharmacol. 2007 Dec 3;114(3):355-63 examined the antinociceptive effects of Humirianthera ampla Miers. The findings were most interesting. The extract did have an action against chemical pain but not thermal pain. That is to say, ORAL extract “dose-dependently inhibited glutamate-, capsaicin- and formalin-induced licking”. It did not benefit the tail flick response to radiant heat.

In nerve injury pain, we are concerned with neuropathic pain, ie. chemical pain. Nociceptive pain, such as normal pain from excess heat is different. Therefore, failure of Humirianthera against normal or nociceptive pain does not necessarily indicate it would not have some benefit for nerve injury (neuropathic) pain.

If you review the lists of plant extracts against pain, the natural question is why more has not been done to pursue these leads. The answer of course is money. Of particular frustration has been the slow progress with resiniferatoxin, an extract of a Moroccan cactus, which is known and proven to destroy the TRPV-1 channel. It continues to be a disappointment that no scientist has injected resiniferatoxin locally in the vertical lineup of dorsal root ganglia, or even the dorsal root entry zone, in order to destroy the TRPV-1 channels which are central to the hypersensitization which characterizes central pain. We have wtitten to a number, with the request, but there have been no willing respondents.

Perhaps the lab work on resiniferatoxin is being done by PhD’s who do not feel competent to perform clinical work. The M.D.s, on the other hand, may not feel competent in the biochemistry of resiniferatoxin. Perhaps the undesirable sequelae associated with laminectomy is being transferred onto the simpler maneuver of merely injecting the DRG without removing bone. We have not even seen resiniferatoxin for “at-level of injury” pain.

It is surprising this has not been tried in animal models. The market for peripheral nerve injury pain is much greater, but the need for help is even larger in central pain (which is to say that elimination of pain in a body part is less daunting than eliminating pain in the entire body, potentially). No one who has watched someone in agony from shingles, with pain in a single spinal nerve can doubt that they merit any help possible; but what about a patient who has identical pain in all spinal and most cranial roots bilaterally?

It is clear that a funding shortage continues. Since the topic is severe pain, it seems that irrespective of scientific interest, humanitarian motives would drive more money into the field. We thank the companies which are studying pain. CP subjects await a cure.

Ironically, pain medicines are the most profitable of all pharmaceuticals, so it seems that nonparticipating drug companies are shortsighted in not aggressively pursuing the leads. Our thanks again to Kory McHenry for his information on resiniferatoxin, to date.