Thursday, December 06, 2007

MDC Scientists Reveal Role of Gene in Sensitivity to Thermal Pain

The skin is the largest human sensory organ. What is not fully understood is how the skin responds to stimuli, especially to pain. Research by Nevena Milenkovic, Christina Frahm, Professor Gary Lewin and Dr. Alistair Garratt of the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch, Germany, has now demonstrated that Stem Cell Factor (SCF) and its receptor, c-Kit, play a central role in tuning the responsiveness of sensory neurons to heat stimuli. "As yet, c-Kit is the first example of a single gene being required for normal noxious heat sensitivity of C-fibers," according to the neurobiologists. Their paper has just been published online in Neuron *.

Depending on the size of the individual, there are between 1.5 and 2 million sensory receptors in the skin which are sensitive to pain, pressure (touch) and temperature. These specialized sensory neurons, also called nociceptors, detect painful thermal and mechanical stimulation of the skin and transmit the information to the brain, where it is processed and consciously experienced as pain.

"About 40 percent of the skin's sensory receptors are responsible for the perception of pain," Professor Lewin explained. "Receptors sensitive to touch account for only ten percent." This disproportionate distribution of receptors specialized in pain and touch underscores the significance of pain sensitivity. "Without pain receptors," Professor Lewin and Dr. Garratt pointed out, "we would quite probably die of unnoticed injuries at an early age."

Pain threshold for heat is lowered 
Pain receptors are nerve endings – nerve fibers that inform the brain about skin injuries. These nerve fibers have different cell surface receptors. One of these is c-Kit, which the MDC researchers investigated more closely.

To study the characteristics of the receptor in more detail, the MDC researchers bred mice lacking c-Kit. Experiments attempting this were already carried out in the 1950s, but the mice died of anemia very quickly. It was not until the advent of transgenic technology that this problem could be circumvented. Dr. Garratt administered the gene for erythropoietin (Epo) to the mice. Epo is a hormone which stimulates the production of red blood cells. As a result, the mice are no longer anemic and have a normal life expectancy.

If the mice – lacking c-Kit but equipped with extra copies of the Epo gene – are exposed to temperatures that are normally extremely painful, they at first do not react. It takes a temperature of about 6 degrees Celsius (°C) above the normal pain threshold of approximately 41 - 50°C for the animals to respond to the stimulus. C-Kit is activated by Stem Cell Factor (SCF), a ligand that it is expressed in the skin. Therefore, the scientists conclude that also when the skin is injured, SCF is released and stimulates c-Kit, leading to a reduced pain threshold for heat. Consequently, sensitivity to heat in the affected area is elevated, as the MDC scientists observed after injection of SCF and measuring paw withdrawal latencies to a heat stimulus. Professor Lewin explained how this works. "It's like having a sunburn – even lukewarm water becomes painful," he said.

Cancer drug Gleevec (Imatinib) blocks c-Kit – heat sensitivity decreases 
The researchers attained similar results by administering Gleevec (imatinib), a drug that a few years ago revolutionized the treatment of breast cancer, leukemias and gastrointestinal stromal tumors, but also can apparently alleviate pain. Gleevec blocks a specific group of proteins to which c-Kit also belongs.

In the experiments, sensory fibers of wild-type mice expressing c-Kit that were given Gleevec showed the same properties as those of mice that did not express c-Kit: the pain threshold for heat was clearly higher in wild-type mice treated with Gleevec. They were able to bear higher temperatures than the control mice not given Gleevec. Next, the researchers want to investigate if Gleevec really can alleviate pain in patients.

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