Malmberg and Bley, Part II
Turning Up the Heat on Pain, a new work on the TRPV1 channel represents a real breakthrough in understanding the pain process. We continue with the review and commentary. Hopefully, you will be able to purchase a copy of the entire book. These things make wonderful gifts to your doctor. Central Pain should probably be called “Central TRPV-1 disease”.
According to the Malmberg and Bley’s work, drugs like capsaicin and resiniferatoxin are lipophilic (drawn to fat) and therefore may penetrate the cell membrane, which is largely fat, and then move to depot sites inside the cell, where they act on the Three Horsemen of the Apocalypse chemicals discussed in the prior article, namely, anandamide, 12-HPETE, and NADA.
These three are TRPV-1 agonists (activators) and are manufactured naturally in the body. Oddly in the energy minimum state the structure of these three pain chemicals can be superimposed. 12 HPETE can also be superimposed over capsaicin, emphasizing that STRUCTURE is more important than chemical composition. This also indicates that they bind at a locus which is not a single amino acid. There is great interest in figuring out which part of the channel they act at. This could have tremendous therapeutic potential. Currently, the candidate location for action is either at the C terminus or between the second and third domains.
There is also interest in mutations. For example, if a virus could be injected which populated the body with TRPV=1 channels that refused to function, then pain might be blocked. However, ALL mutants of the channel OR of the pore domain, thus far developed, INCREASE sensitivity to capsaicin.
As mentioned earlier, reducing the pH below 6.0 leads to opening of the channel at room temperatures. Acids are thus very important and the pH of the environment of the cell cannot be overemphasized. The IASP has published years ago that it is ironic that the sensation of