The whole process of gene activation is becoming more complicated. It is not all or nothing at all.
Those interested in pain should generally attempt to follow the Journal of Pain. With subscription rates in the hundreds of dollars, the nearest medical library is probably the best bet.
Hathaway and Fitzgerald have reported in J Pain. 2006 Jan;7(1):57-61 on the upregulation which occurs after administration of Nerve Growth Faction (NGF). We have already discussed NGF in prior articles. It is one of four major factors which induce genes to manufacture proteins to cause nerve restoration or growth. This attempt to kick start the dead nerve, or perhaps boost some nearby nerves to “fill in” persists and the gene production of growth factors it induces is thought to be behind central pain, because at least one growth factor, BDNF, shuts off GABA(A), a pain quieter of the nervous system.
This particular study is regarding “secondary” hyperalgesia. As all CP sufferers know, hyperalgesia is a state of the pain nerves which makes them exquisitely sensitive to stimuli, however innocuous, converting the stimulus to pain, sometimes severe pain. In extremely hypersensitized individuals, no stimulus at all is required for pain firing. This is known as “spontaneous” burning, as opposed to “elicited” or “evoked” burning from light touch, temperature change, movement etc. There are other spontaneous or near spontaneous pains, such as lightning pains or pins and needles. “Secondary” refers to an extension of the area of hypersensitization beyond the area injected with some pain causing substance. For example, if capsaicin is injected into a very small skin wheal subcutaneously the area actaully injected will be hypersensitized, due to the effect on C fibers and the TRPV-1 receptors they activate. However, C fiber activity travels to the cord, where they recruit the large well localized rapidly conducting A delta pain fibers coming in from a zone well outside the area where the injected capsaicin infiltrates. Thus, the area of hypersensitization spreads beyond what is expected from the initial area of injection, which is “primarily hypersensitized”. This spread refers to “secondary hyperalgesia”. It signifies that A delta fibers have been enlisted in the cause. A deltas are powerful and that may be why evoked pain is ever so much more severe than spontaneous burning. A given person may have one or the other, but usually has both spontaneous and evoked burning. Evoked burning makes the diagnosis of central pain easy, since light touch causes instantaneous pain in peripheral nerve injury, but there is a twenty or thirty second delay in the evocation from injury of central origin. It would be very intersting to know what is going on in that twenty seconds, presumably some kind of gene activity which quickly leads to pain proteins.
So far, this is pretty much old hat stuffy, thoroughly worked out by Tony Yaksh at UCSD. The study by Hathaway and Fitzgerald points out a new method of hypersneitization, by the injection of a growth factor. It is easy to understand why the secondary hyperalgesia would subside when the capsiacin wears off. What is unique here is that the hyperalgesia is occuring right in the genes. Something about NGF has swtiched on the protein factories and the pain amino acid precursors which will be asembled into peptides and then the pain protein chemicals which begin pouring out. Ordinarily such assays look for messenger RNA, as an easy way to predict the ultimate outcome. BUT, NGF effects only lasted for about sixty minutes. It was temporary.
A novel method was used to detect the neuropathic pain. An electrode was inserted into a leg muscle of the rat and activity in the muscle as measured by EMG was taken as a withdrawal effort which was caused by gentle stroking of the fur on the leg with a brush. This is very innocuous, the brushing of fur, and does no muscular excitation is measured on EMG in normal animals. What is clever is that it detects lesser muscle events as a reaction to pain than mere visual observation.
In other words, we have something that at first gloss looks similar to Central Pain, except it disappears. Thus, it is not really a good model. It may be a model for evoked burning, but it does not go to the core problem, which is permanent hyperalgesia. Perhaps in some fashion light touch gains the power to “evoke” extra pain, after the twenty seconds of Mitchell’s delay seen in central but not in peripheral nerve injury pain. Whether this evocation is linked to NGF is not known.
However, we must notice then that there is both temporary and permanent hyperalgesia. An analogy might be in the dopamine II receptor. Amphetamines lock on to this receptor so powerfully that they remain locked on permanently. The protein is changed, similar to the way you can cook an egg, but you cannot uncook it. Even if the chemicals are the same, the protein structure is not. Eventually, the cell cannot manufacture sufficient DII receptors to make up for those “tied up” and the result is Parkinson’s disease. NOT ALL PARKINSON’S PATIENTS HAVE USED AMPHETAMINES, ONLY A SMALL MINORITY FALLING IN THIS CATEGORY.
Still, something seems to be going on here. NGF is temporarily firing up pain sensitivity, whereas in Central Pain, the receptors STAY fired up. Central pain is nearly always permenent. What is the event, what is the chemical which is responsible for the chronic maintenance of the high rate of production of pain exciters. We do not yet know enough about gene regulation to answer this question. BDNF seems to be the growth factor of interest in CP, especially its NR1 subunit receptor. However, the temporary behavior of NGF bears watching. Since in this study the material is exogneously produced, it is probably NOT acting solely via genes, but in a direct fashion. If we can identify the target, perhaps we will learn more about the “for all time” fixation which occurs in central pain. Central Pain is unmatched for its durability as a pain state. It is also the most resistant to treatment. There is something terrifyingly fixed in CP. The person is suspended in pain. She can have it evoked further by light touch, temperature change, or movement, but cannot have it eliminated.