It looks like BDNF is one growth factor which runs uphill.
Obata and Noguchi, reporting in Neurosci Res. 2006 Mar 2 have demonstrated that the increased BDNF in nerve injury comes from cell bodies in the dorsal root ganglion OUTSIDE the cord. BDNF moves into the cord from the DRG and then ONWARD and UPWARD toward the brain (termed “orthodromic” migration) to exert effect inside the cord in the dorsal horn, or second order neurons.
The “dorsal horn” is some anatomists idea of what the Rexed layers look like on cross section when stained with a silver stain. Because the Rexed layers are not myelinated (grey matter), they also show up on MRI looking like a circle in the middle of the cord, surrounding the central canal, which then has four spokes radiating out like “horns”. Think of it as a roundabout with four roads, two leading in and two leading out at an angle. The roads in back reminded early anatomists of horns.
These “horns” represent the intake of neurons from the back or dorsum of the cord, and the outflow of information to the body through the front of the cord. In the back, the incoming cells terminate in zones, or layers called “lamina” [Latin for layer] by a scientist whose name was Rexed. Dorsal horn simply means the area where neurons move into the cord, and in the case of spinothalamic pain fibers, having received the input, cross over to the other side before they ascend to the thalamus (brain). Layer I is the marginal layer and these apparent C fibers can by action of a single neuron sensitize huge portions of the body.
Layer II is the substantia gelatinosa where virtually all C fibers ascend to the thalamus, so Layer II is the pain layer in the cord. C fibers are small and slow and so their craft is in causing the release of pain exciters which in turn activate or recruit the big powerful A fibers. A fiber pain is BIG pain. Some of the sensitizing fibers, especially in Layer I can ascend on the same side as they entered. It is not clear what advantage crossover has for nerve fibers, but they certainly do it. BDNF originating in the dorsal root ganglion, which is the collection of cell bodies whose axons reach the skin, moves into the cord along the dorsal horn, where it wreaks havoc by eliminating the possibility of inhibition of pain by GABA(A). Patients with central pain have sensory loss to one degree or another. Any remaining fibers have one option, not to signal at all, or else to signal pain. If you have central pain, you know which option they exercise. They exercise the alarm function signalling nerve injury. This is why you have spontaneous pain, with no stimulus whatsoever to your skin.
The authors report that “it is now known that the activation of mitogen-activated protein kinases [MAPK] occurs in these sensory neurons and contributes to persistent inflammatory and neuropathic pain by regulating BDNF expression.” Many sensory neurons are capable of sending either a pain excitatory or pain inhibitory message on up to the thalamus (brain). You recall that BDNF blocks GABA(A), which is a pain inhibitor at the synapse, leaving the cell with just one option, pain excitation. THIS, then is YOU, if you have CP. Without p38MAPK, your BDNF could not work its way.
By way of review, nearly everything in the synapse requires activation by a kinase (kinases perform attachment of a high energy phosphate bond) including the MAP kinases, so we must be aware of MAP kinase kinases. Just how far back this goes can get dizzying. It so happens that MAPK can SELF-phosphorylate by interacting with MAP3K7IP1/TAB1 protein, OR it can be activated by MAP kinase kinase. MAPK can be phosphorylated at site 38 by either threonine or tyrosine. Since, among nerve cells, tyrosine kinase A is found ONLY in pain neurons, we are mostly interested in p38 MAPK. (Note: TrkA is the target receptor for BDNF–although only found in neurons which are capable of generating pain, BDNF and TrkA are also secreted by the cumulus granulosa cells, the cells immediately around the oocyte, and do increase the number of oocytes which will reach maturity during in vitro ferilization).
It seems obvious that blockade of either tyrosine linkage in p38 MAPK, blockade of MAP3K7IP1/TAB1 protein or direct BDNF blockade “could provide a fruitful strategy for the development of novel analgesics”