MDC Scientists Reveal Role Of Gene In Sensitivity To Thermal Pain

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MDC Scientists Reveal Role Of Gene In Sensitivity To Thermal Pain

http://www.medicalnewstoday.com/articles/90962.php

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, Frahm, Professor 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.

*Nociceptive tuning by Stem Cell Factor/c-Kit signaling

Nevena Milenkovic1,3, Frahm1,3, Max Gassmann², Carola

Griffel1, Bettina Erdmann1, Carmen Birchmeier1, R. Lewin11,*,

Alistair N. Garratt1,*

1. Max Delbrueck Center for Molecular Medicine,Berlin, Germany;

2. Vetsuisse Faculty and Zurich Center for Integrative Human

Physiology, Zurich, Switzerland

3. authors contributed equally

http://www.neuron.org/

http://www.mdc-berlin.de/~gfactor/