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Painful but less

Weizmann Institute of Science scientists have discovered a protein that regulates pain sensitivity throughout life

The dedicated gardener: Kif2a protein deficiency led to wild growth of nerve fibers in the skin of adult mice (right), while in mice without the protein deficiency the nerve endings were carefully nurtured (left)
The dedicated gardener: Kif2a protein deficiency led to wild growth of nerve fibers in the skin of adult mice (right), while in mice without the protein deficiency the nerve endings were carefully nurtured (left)

Similar to trees that grow tall tops in order to sense the sunlight, our sensory nerve cells - those whose job it is to gather information about what is happening in and around the body - grow branched nerve extensions called axons. These extensions are spread throughout the body and transmit different sensations in response to various stimuli. But who is the dedicated gardener who keeps the branches from growing wild for years? In the article thatIt was published in the scientific journal Cell reports, revealed Prof. Avraham Yaron and his colleagues in the Department of Biomolecular Sciences and the Department of Molecular Neurobiology at the Weizmann Institute for Control Protein Science, which is responsible for nurturing the branching of the nerve endings. Their findings shed light on the mechanisms that regulate our sensitivity to pain throughout life and may teach us about possible ways of dealing with pain.

The nuclei of the sensory nerve cells are planted next to the spine, and in order to perform their function properly, each of them grows a nerve branch that splits into two at the beginning: one branch grows towards the central nervous system, while the other branch spreads to the different parts of the body. These extensions reach a great length - the longest in which they spread from the lumbar vertebrae to the foot - and when they reach the outer layers of the skin, they further split into branched tops that monitor heat, pain, touch and other irritations. 

בA 2013 study Prof. Yaron's research group discovered that a structural control protein called Kif2a is required for the "pruning" of the nerve extensions during the development of the nervous system in mouse embryos, and that in the absence of the protein, an excess of them is formed in the skin tissue. In the new study, a team of scientists led by research student Swagata Dey examined what happens in adult mice. To this end, the researchers first had to face a significant challenge: mice cannot exist without the gene that expresses this control protein, so they had to develop through genetic engineering a mouse strain in which this gene is silenced, but only in the sensory nerve cells.

Using these transgenic mice, the scientists discovered that the control protein continues its gardening activities even after birth, and showed that a lack of protein led to wild growths: each parent branch split into more daughter branches. In fact, the researchers detected a slight increase in the density of nerve cell projections in the skin of one-month-old mice without the gene, and three months later the condition branched out and worsened. The researchers concluded from this that the activity of the protein in the sensory nerve cells is important throughout life and that its deficiency becomes more noticeable with age.

""What we identified is a kind of 'exposure therapy', that is, the continuous exposure to pain, led to a decrease in sensitivity to the pain-causing stimulus"

But did the lack of protein also affect the sensitivity to stimuli and pain? "In the first month after birth, the mice did not show hypersensitivity to stimuli in the various tests we performed, despite the increase in the density of axons in their skin," explains Prof. Yaron. "However, after three months they showed hypersensitivity to pain and heat, the intensity of their reaction to these stimuli increased and so did the duration of the reaction, while the sensitivity to touch did not change." 

In order to examine whether the increased sensitivity to pain is related to the structural change in the nerve endings, the researchers collaborated with the laboratory of Prof. Alexander Binstock and research student Dr. Omer Barkai from the Hebrew University of Jerusalem, who developed a computer model of the relationship between structural changes and neural activity. The model suggested that the structural changes in the nerve endings could explain both the increase in the intensity of the response and the extension of the duration of the response.

Pain now, relief later

In order to substantiate the findings, the scientists engineered mice in which the control protein is missing only in sensory nerve cells that express a known receptor involved in pain perception: the capsaicin receptor - a fatty substance responsible for the spiciness of chili peppers. When the same cells were activated, the mice showed hypersensitivity and behaved in a way that indicated an increase in the sensation of pain.

But the most surprising discovery was revealed six months after birth: while the density of axons remained high, the hypersensitivity to pain disappeared. "Most of the researchers we consulted with did not understand at all why we are testing the mice even at the age of six months," says Prof. Yaron. "However, in the end, this re-examination at an older age revealed that the body activates a compensatory mechanism throughout life, designed to deal with the many axon ends in the skin by reducing the sensitivity of the nerve cells." 

To understand how the compensation mechanism works, the researchers sequenced the RNA molecules in the sensory nerve cells and mapped the changes in the expression levels of the various genes. They recognized that at the age of six months there is a decrease in the expression of some proteins that play a key role in transmitting the sensation of pain. Using the computer model, they showed that the changes in the expression levels of these genes are sufficient to compensate for the hypersensitivity caused by the excess of axons. 

"Although the silencing of the control protein leads to an increase in pain sensitivity in the short term, it is possible that thanks to the compensation mechanism it is possible to gain a decrease in sensitivity in the long term," says Prof. Yaron. "What we identified is a kind of 'exposure therapy', that is, the continuous exposure to pain, led to a decrease in sensitivity to the pain-causing stimulus. A better understanding of the compensation mechanism that lowers pain sensitivity may be good news for those suffering from chronic pain."  

Dr. Irina Gochman, Sapir Suissa and Dr. Andrew Kovalenko, from the Department of Biomolecular Sciences and the Department of Molecular Neurobiology at the Institute also participated in the study; Dr. Rebecca Hefner-Kraus from the Department of Veterinary Resources at the Institute; Dr. Noa Vigoda, Dr. Esther Feldmaser and Dr. Shafra Ben Dor from the Department of Life Science Research Infrastructures at the institute.