Central Pain: You Must Read This

Lawson and coworkers have laid out two successive studies of major importance in the Journal of Neuroscience. Since this journal is fabulously expensive, we thought you would like to have a summary here. Basically, three cheers for Sally N. Lawson. We hate to get you too far ahead of what is available clinically to your doctor, which makes both of you nervous, but researchers are speaking of KILLING nociceptors permanently.

If you have been reading here, you will have noted that we have identified Nav 1.3 as a FETAL ion channel, which indeed it is. However, it does persist in very low levels in pain neurons. All the Nav channels are thought to be present in very low levels in normals, but Nav1.3 comes on strong at specific times during fetal life, presumably to make the fetus more sensitive to positional pain, to protect its joints, etc. Nav 1.8 is the major sodium channel in adults and some scientists have stated that it does NOT participate in Central Pain. We precede this review of Lawson’s latest article by mentioning that, since her work has focused on Nav. 1.8.

However, the presence of Nav1.3 in the DRG of central pain patients does NOT rule out the likelihood that once the big A alpha/beta nerves have been recruited that they may utilize their functioning Nav1.8 channels to explode the pain signal. In that sense, Nav1.8 may well participate the central pain, so the phrase “does not participate” must be read in the proper context. We have referred to Nav1.3 as a fetal channel to help you understand the focus on its surprising, unexpected, MAJOR appearance in Central Pain in adults. By comparison, adults are considered to be governed by the Nav1.8 sodium channel, which does NOT, according to existing theory, participate in central pain.

You remember that the sudden flow of sodium into the cell while potassium flows out, as well as sodium/calcium exchange at the neuronal membrane, are what is behind an action potential, or nerve firing.

The movement of these charged ions generates the voltage which travels up the pain nerve. The frequency of neuron firing determines the degree of pain. A “neuron” is an individual cell,while a “nerve” is a group of cells. The cells vary in nature according to size (diameter) and degree of myelination. Size and myelination determine speed with which the signal travels up the neuron. The big fast fibers are A fibers (alpha and beta), the medium sized fibers are A deltas, and the tiny unmyelinated slowpoke neurons are called C fibers.

Sally Lawson and others from the well respected pain research institute at Bristol See J Neurosci. 2005 May 11;25(19):4868-78, identified tyrosine kinase A (TrkA) as a marker for a nociceptor, ie. a neuron dedicated to pain signal. It did not matter whether it was one of the big A alpha/beta pain fibers, the medium A deltas or the small C fiber, trkA appeared to designate which fiber was after pain. Let us say that again, Lawson’s finding was that trkA is a marker for a pain dedicated neuron whether the neuron is the tiny C fibers or the huge A alpha/beta fibers. Probably more surprising was their finding that the frequency of trkA and the Nav1.8 channel was NOT greater in C fibers than it was in the occasional A beta fiber. ALL the neuron groups appear to have a proportion with trkA and Nav1.8, linked to Nerve Growth Factor (NGF) which are set up to do the pain work. (Dr. Lawson also reported that the trkA Nav1.8 action potential lasts LONGER than in other channels, but since pain intensity has long been considered to be dependent on FREQUENCY of firing rather than the magnitude of any particular action potential, the significance of the lengthened Nav1.8 channel action potential is still not known)

More interestingly for us, the more trkA a neuron contained, the greater numerically was the presence of the Nav1.8 channels. Embryologists have long puzzled over neuron differentiation. How is it that some neural crest cells turn into nociceptors (can detect pain) and some turn into other types of sensory neurons. For example, there are quite a number of different Trk’s depending on the subclass of the sensory neuron populations. Researchers have now come to realize that there are complicated gene cascades throughout the genome. The development of one gene is necessary for the expression of another. This makes the relatively small number of coding genes sensible since the combinations and permutations of expressing genes leads to a vast potential for variety. Marmigere et al at Karolinska have reported in Nature Neurosci. 2006 Jan 22 the discovery that neurogenin-2, a proneural gene program, promotes sensory specialization, but it does not specify which neuron will become a nociceptor. However, one of the Runt transcription factors, Runx1 “promotes axonal growth, is selectively expressed in neural crest-derived TrkA(+) sensory neurons and mediates TrkA transactivation in migratory NCCs.” In other words, Runx1 makes nerve processes grow, is manufactured in TrkA neurons, and even induces migratory cells from the neural crest to begin to manufacture TrkA, presumably transforming them into nociceptors. Blocking of Runt expression causes nociceptor cells expressing TrkA to stop making TrkA and to DIE!!!!

Furthermore, Takatori et al have reported in Anesth Analg. 2006 Feb;102(2):462-7 that “Local anesthetics (LAs) suppress sympathetic sprouting, which correlates with neuropathic pain. However, the precise mechanism of the suppression is unknown. Nerve growth factor (NGF) contributes to the sympathetic sprouting, and NGF signaling starts with NGF-stimulated autophosphorylation of TrkA, which is a high affinity receptor of NGF” A “neurite” is a nerve process such as an axon or dendrite. Takatori found that a number of different local anesthetics such as lidocaine or procaine (ie. both amide and ether linked local anesthetics) suppressed nerve outgrowth AND TrkA without any toxic effects on the cell. This makes Lawson’s work so very important.

We have been so bold here previously at this site to subscribe to the suggestion by Bryan Hain at Yale that Nav1.8 WAS the ion channel of adult pain, and Nav1.3 the channel of chronic pain, although of course the other channels are necessary to complete the pain process including the oft written about TRPV-1 channel as well as CaV2.2. A number of voltage currents are necessary for the generation and regulation of action potentials (neuron firings). Think of an action potential as a spike on an oscilloscope indicating the frequency of something, in this case the frequency of action potentials in a pain neuron. The spike represents voltage change so that the polarization or difference in voltage between the outside and inside of the cell for an instant is overcome, indicating current flow.

PainOnline has also subscribed to the evidence from Tony Yaksh at UCSD which showed that signal in injured C fibers travels to the cord, sensitizing and recruiting the big A beta and other rapid large pain neuroceptor neurons (you can find these discussions using Search for Tony Yaksh or “recruit” at this site). The sensitizing is in part retrograde, in that an Abeta sensitized at the cord experiences chemical changes which make it more reactive back down at the skin site to which it is devoted. Here then is a mechanism for injury in one area to cause heightened sensitivity in a different area. Of course, C fibers may sensitize other C fibers as well as the big A fibers.

We have also written about the findings of Marshall Devor, reported in the book, “The Axon”, wherein he demonstrated that injured nerves release a substance able to induce spontaneous pain firing in uninjured neighbor neurons, which Dr. Devor, who is a correspondent to PainOnline has called “crossed afterdischarge”. (find using “afterdischarge”)

Now Dr. Lawson has taken a second, more specific step in showing that once pain hypersensitization occurs, for example in the dorsal root ganglion just outside the cord, that the resulting BIG pain is carried by the BIG fibers, ie. sensitized pain is mainly a matter of recruitment.

Now here is the astounding part. She out-Devor’s Devor. She finds evidence that the impetus sensitization of normal pain carrying neurons comes from not only from injured neurons but also from DEAD neurons, or at least from the glia surrounding DEAD fibers. Although this idea has existed in more or less unformed theories, The extra and surprising claim by Dr. Lawson is that she pins the NGF initiating process directly on injured and even DEAD neurons. Devor had already shown this for injured neurons. Since all with central pain have plenty of dead and injured neurons, we think maybe she is our woman.

All of this is consistent with what has been written here, so consistent in fact, that is as much a summary as it is a radical new finding, with the extension to DEAD neurons, being something SHE can lay claim to. What it basically means is that we should stop focusing so much on the neuron and consider the proteins put out by the glia AROUND neurons. THEY make NGF, BDNF, and the other growth factors. No one has synthesized this matter as well as Dr. Lawson, and she deserves recognition for reporting that the signal comes from inflammation generated by injured neighbor or DEAD neurons.

In cord injured patients then, it would appear that even dead cells can initiate inflammation, about which there are numerous articles at this site to give background. It is also possible than SCI patients have injured cells which do not transmit signal, but are capable of generating Nerve Growth Factor (NGF) production in surrounding glia. (there are many prior articles about glia at this site, especially recently on the microglia).

So much emphasis has been placed on inflammation here that we grow cautious, fearing that inflammation is not the entire story, and hope the researchers will continue to thread out the other orphan proteins in pain neurons, to see if there is not more to the story. Dr. Lawson seems to accept the currently predominant theory that inflammation is the story, and possibly this is correct, but it only seems prudent to study the other proteins present whose function has not been identified.

With that minor qualification, we are very impressed by Dr. Lawson and coworkers who seem almost awesome in the breadth by which they handle the ion channels and kinases, and wonder where on earth they got funding to study ALL those chemical processes. Not a few scientists in the U.S. would be glad for the funding to study ONE of those entities. Thanks to the U.K. companies and/or government agencies which are carrying on the work in pain.

That her findings are consistent with what we have been saying here over the years, allows us to take a little satisfaction as well; although of course, nothing should ever be taken away from the hard work of the bench top researchers who are the real heroes of medicine.

For those of you in the U.K, here is something to be very proud of, and of course it was the work of Patrick Wall from London who started the huge interest in pain which has benefitted the entire world. Dr. Wall also was the originator of this database, so we pay tribute once again to his progeny in the U.K. and his intellectual issue all over the world, as well as those who inspired Dr. Wall and worked with him, such as the inestimable Dr. Ron Melzack. We are also grateful for the continued elegant work at Karolinska and for the highly pertinent studies from the University of Kyoto, Japan.

If you can get a copy of Dr. Lawson’s recent article in the current issue of J. Neuroscience it is worth reading, for its content, and also because like nearly all the British, they write well.