Why don’t we just give a big bunch of money to Dr. Hulsebosch and let her work pain out? In this article we review a study of central nerve injury pain and one on peripheral (DRG) nerve injury pain.
We have praised Claire Hulsebosch at UTMB at this site as much as we could possibly praise anyone and her continued work shows this was justified. She and her group have recently confirmed in Exp Neurol. 2006 Feb 12 that “increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury.” If you have been reading anything at this site, you are already very familiar with ERK, MAPK, and CREB. You can use SEARCH if you desire more information.
This finding by Crown et al should shock no one. It is merely corroborating the mechanism of hypersensitization of the spinal cord in nerve injury of CENTRAL origin. It is noteworthy since most studies have looked solely at the peripheral nervous system, injury to which produces the same pain chemicals. The authors include Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE.
These authors showed that “rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP)”
Note that the injury to the rats was MODERATE. It is, after all INCOMPLETE cord injury which leads to Central Pain. Ordinarily, clinical motor loss, while common, is not absolutely necessary to form central pain. However, studies such as SSEP which can show subtle motor loss seem to indicate some motor injury is exceedingly common in those with Central Pain. By comparison, using von Frey hairs, it is ALWAYS possible to demonstrate some degree of loss of superficial sensibility (touch temperature, topoesthesia etc) when Central Pain occurs.
Remember from the repeated articles here on the topic that activation of proteins means attachment of a high energy phosphate bond, or phosphorylation, which is done by kinases.
Crown, et al showed “upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury” shows a relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)).” Note that the authors were SPECIFICALLY studying the SPINOTHALAMIC tract neurons. These are in the anterior cord.
As is well known, not all, in fact the minority of humans suffering Spinal Cord Injury develop Central Pain. The rate for full CP in SCI is perhaps one in fifteen, although as many as seventy percent of SCI patients will describe some sort of chronic pain after SCI. Crown states: “Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP.”
Now comes the real discovery, “The results indicate that activated kinases such as pERK 1 and pERK 2, p38 MAPK, but NOT pJNK [phosphorylated c-Jun N-terminal kinase is a stress associated kinase associated with ceramides which are lipid second messengers resulting from the breaking apart of sphingomyelin and could be expected in cord injury], are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP.” In other words, OTHER kinases associated with cord injury such as pJNK do NOT correlate with the later formation of Central Pain, but ERK, MAPK, and CREB do correlate.
SOME protein kinases hypersensitize the pain pathway and others do not. Since when TNF is around, NF-kappaB seems to preserve cell survival, and JNK causes cell death, we wonder which is in the interest of the Central Pain patient. Some of these studies seem to suggest prevention of appropriate death of injured neurons by NF-kappaB may work to prevent the housekeeping action of Tumor Necrosis Factor. The NF KappaB preserved cells may be at the heart of central pain generation. They are perhaps “incompletely dead”, and can only cause agony.
The authors conclude, “In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.”
We quote a great deal from the authors here because they are so lucid and definite in their statements. This information does not draw into question anything you have already read in the articles at this site, but what Hulsebosch and group at UTMB have shown is that these pain exciters ONLY appear in cord injured rats which subsequently develop central pain.
In other words, if you have central pain, you are unlucky enough to have followed the same chemical cascade of pain exciters as the CP rats in this study. It is important to note that hypersensitization is NOT universal after SCI. It is equally important to note that when the pain kinases come on, so does Central Pain.
Thank you Dr. Hulsebosch, again, for your continued hard work, and for your support for those directing this site.
Of similar interest is the recent study in Eur Spine J. 2006 Feb 11;:1-9 by Ozaktay AC, Kallakuri S, Takebayashi T, Cavanaugh JM, Asik I, Deleo JA, Weinstein JN on the effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor (cytokines already the focus of numerous articles at this site) on sensitivity of dorsal root ganglion and peripheral receptive fields in rats
These substances are known as pro-inflammatory cytokines. Although we have hinted that pain exciters come from the neuroglia around neurons, Ozaktay identifies injured discs as the origin of at least some of these cytokines. This suggests a possible role of disc injury in the development of Central Pain in SCI patients.
BOTH the dorsal root ganglion AND the receptive field on the skin showed increased mechanosensitivity (to touch) when these substances were applied to the DRG. The DRG contains cells bodies of neurons reaching for the cord, so material is being produced in the cell body, which then drops down to nerve endings near the skin, to produce hypersensitivity there as well. This is consistent with the work from Harvard and Mass General (Woolf and his colleagues) which showed molecules being produced in cell body and “snowing” down on the nerve endings. (see prior article here).
This study was a short term study, done over a short time, but it takes little imagination to realize that if TNF and the interleukins studied continued to be produced, the hypersensitization would continue. The linkage to injured disc in this study is interesting and we may be seeing more study on how important disc injury is in inflicting central pain in spinal cord injured patients.