Central Pain: We have no choice but to love our expensive friends.
Merck has long enjoyed the reputation of being the real thing when they set their mind to a research problem. Now that they are eyeing pain, we can only declare, “Yes!!!!!” No matter what the world says about drug companies, since they have a lower profit margin than those who sell bottled water, we still love them. They have amazing scientists. If the execs would hire a few more of them they could make better profits, sell more stock, and hire more scientists.
Some wonderful news. Liu and other scientists at Merck have figured out a way to grow and assay the Nav1.8 channel. We have already stated that sensitization in NORMAL adults comes via the Nav1.8 channel. Nav1.8 is sometimes also called the “Tetrodotoxin resistant” ion channel, but testing with tetrodotoxin is clumsy and time consuming. Nav1.8 is typically found in the small C fiber type of neuron, in other words, the sensitizer fibers. These channels are also found wherever small diameter sensory neurons are found, including the heart.
In Central Pain, an abnormal sodium channel, Nav1.3 populates the Dorsal Root Ganglion and Dorsal Horn. More recently these fetal Nav1.3 channels were found by Waxman and Hains clear up in the THALAMUS.
Although Nav1.8 is not thought to drive central pain, it nevertheless drives a lot of sensitization in ordinary people, including quite possibly, peripheral neuropathic pain. Blocking Nav1.8 is surely a stepping stone to blocking Nav1.3.
Liu et al report in Assay Drug Dev Technol. 2006 Feb;4(1):37-48 that Nav1.8 channels can be grown in cultured mouse embryonic kidney cells. Better yet, they have developed an assay using a “membrane potential, fluorescence resonance energy transfer-based functional assay on a fluorometric imaging plate reader (FLIPR((R))-Tetra, Molecular Devices, Sunnyvale, CA)”.
This means that the plate reader can measure membrane potential to reveal the gross Nav1.8 effect, an effective way to measure the number of channels. Growing these channels and measuring their activity is a BIG step toward developing subtypeselective blockers. The Merck scientists chose to include the beta1 subunit in their cultured channels because they believe this subunit is highly pertinent to the pain function of these channels.
The assay method, which is also known as FRET (fluorescence resonance energy transfer), should permit Merck and other scientists to look specifically at subunit function, hopefully developing compounds which stop the pain function without threatening needed sensory transmission to the heart. Understanding subunits is an important part of ending neuropathic pain. One of these days, we are all going to yell “FACE” at pain, and Merck may very well be the drug company to do it for us. Go Merck!
