CGRP, calcitonin gene related peptide, has gotten lots of play because it is known to cause BDNF release in trigeminal neurons, which are thought to cause migraine. Big money is on the line.
Sequence is important, CGRP leads to NGF, which leads to brain derived neurotrophic factor (BDNF) which inactivates GABA. This prevents inhibition of pain. Given the seesaw relationship of pain exciters and pain inhibitors, if you block inhibition, you nearly guarantee pain excitation. The link between Nerve Growth Factor and BDNF, which then blocks GABA, is fairly recent information. Now we learn that NGF is itself kicked into gear by CGRP. Very complicated. CGRP>NGF>BDNF>GABA blockade>neuropathic central pain.
See eg. Buldyrev I, Tanner NM, Hsieh HY, Dodd EG, Nguyen LT, Balkowiec AJ Neurochem. 2006 Oct 25; “Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons.”
These studies were only done in the head. Whether CGRP is similarly active elsewhere in the central nervous system is not known, but for those with central pain, studies inside the head are most important to us. The descending tract of the trigeminal nerve (Cranial Nerve V) drop down into cord and its’ low nucleus (collection of cell bodies) there is termed the subcaudal nucleus. Subcaudal is about as low as you can go and still be talking about pain fibers from the face, so we are really talking about the point of union between facial pain fibers with body pain fibers in the substantia gelatinosa or Rexed layer II of the cord. This linkup is usually somewhere in the region of C3-C5 (individual variation exists), just before combined pain tracts travel back up toward the brain (thalamus).
There is no awareness why pain tracts from the face do a “Here we go loop de loop” downward into cord to join body pain. Motor fibers of CN V connect directly to the brainstem without dropping and so do TOUCH sesnory fibers to the face. We don’t know why pain fibers of CN V DROP before coming back up to the brainstem and onto the thalamus, but they do. Touch sensation does not do this so somewhere during embryonic life, touch and pain from light touch separated. That is why we have what is called “dissociative” loss of sensation, with pain not necessarily corresponding to touch, although surprisingly there is a very close correlation. Again, we are talking about the face and front 2/3 of the head here, as well as the dura which surrounds the brain. Motor tracts of CNV supply the tensor tympani and we have had reports of inability to hear low tones after SCI which ultimately led to central pain.
Buldeyrev et al found that “:depletion of intracellular calcium stores with thapsigargin blocks the CGRP-mediated BDNF release. depletion of intracellular calcium and thereby prevents the action of CGRP”.
This may turn out to be pretty important. Shutting off BDNF is potent anti-algesic stuff. As to side effects, we just don’t know yet. people already think CP patients are a bit off. If they wind up giving us thapsigargin, we just hope they can think up a trade name that will give us credibility, like “Celemood” or something a little less troglodytic than thapsigargin.
Thanks to the scientists who do this work. They are the ones we depend on and our gratitude grows for the difficult and thankless work they perform. The liberation army is making its way to the gates of Pain Auschwitz. We thrill at the rockets that go buzzing over our heads, the sounds of airplanes, and the advancing artillery of anti-allodynic chemicals. The Screaming Eagles of science are trying to rescue the screaming patients with central apin.