A new approach to the development of chronic pain treatment

Weizmann Institute of Science scientists have identified a molecule that transmits pain signals in the peripheral nervous system

About a quarter of the world's population will suffer from chronic pain at some point in their lives. Unlike acute pain, such as that caused by a hammer blow to the finger, chronic pain does not necessarily have a definite cause, and it may last for years or even a lifetime. Chronic pain may damage mental and physical health and lead to decreased work capacity and drug addiction. In a new study published today in the scientific journal Science, Weizmann Institute of Science scientists offer an original approach to treating this problem by focusing on the pathway for transmitting pain signals in the cells of the peripheral nervous system.

The sensation of pain begins in the nerve cells that transmit information from the skin to the central nervous system. Damage to these sensory nerve cells, as a result of disease or injury, may cause a "short" - that is, sending pain signals incessantly for no specified reason. Prof. Mike Feinzilber from the Department of Biomolecular Sciences at the Institute researches molecules that carry protein signals in sensory neurons. These molecules, known as importins and found in every cell, function as cargo carriers that are transported into the cell nucleus, thus effectively controlling access to the genes located in the nucleus. This role of the importins has a unique meaning in the peripheral nervous system: the cells that make it up are extremely long and thin, and the passage of molecular messages from the nerve endings to the cell nuclei can take many hours or even days.

To test the involvement of importins in chronic pain, the researchers, led by Dr. Letizia Marbledi from Prof. Fainzylver's research group, examined mice carrying different mutations in importins; These mice were engineered in the laboratory of Prof. Michael Bader at the Max Delbruck Center in Berlin, which was a partner in the research conducted with the support of the European Research Council (ERC). Following the experiments, the researchers discovered that a certain importin (alpha-3) is actually the only importin involved in the control of pain signaling pathways.

The compounds we have identified are a kind of fast track for drug treatment of pain - proof that it is possible to use drugs that have already been approved for other purposes, to treat chronic pain sufferers. Since the safety of these compounds has been proven in humans, clinical trials for the new use are already possible in the near future."

Next, the researchers sought to identify the gene expression pattern associated with chronic pain, and examine how this pattern is related to the activity of importin alpha-3. Analyzing the differences in gene expression patterns between normal neurons and neurons that do not have importin alpha 3, drew the researchers' attention to a protein called c-Fos that is brought into the nucleus by importin alpha-3. This protein is a transcription factor - a molecule that increases or decreases the expression of genes - and further experiments showed that it accumulates in the nucleus of peripheral nerve cells in mice suffering from chronic pain.

The researchers used specific viruses to reduce the levels of importin alpha-3 or c-Fos in the cells of the peripheral nervous system in mice. As a result, the mice showed significantly reduced responses to chronic pain conditions. Further examination revealed that while alpha-3 importin is essential in signal transmission in chronic pain conditions (as opposed to acute pain), c-Fos is also involved in acute pain, but in these conditions it enters the cell nucleus in other ways. This fact indicates that blocking the activity of importin alpha-3 may be particularly suitable for the prevention of chronic pain.

The next step in the research was to check if it was possible to translate the findings into a medical application. For this purpose, the researchers turned to a special database: the connectivity map (CMap) of the Broad Institute in Massachusetts, which reveals connections between drugs approved for use and gene expression patterns. This database allowed them to identify about 30 drugs that may target the signaling pathway they found; Nearly two-thirds of the compounds they identified had not previously been linked to pain relief. The research team chose two of them - a drug to treat heart failure and an antibiotic drug - and tested them in mice. Injecting the compounds into mice was indeed found to alleviate symptoms of neuropathic pain.

"The compounds we identified are a kind of fast track for drug treatment of pain - proof that it is possible to use drugs that have already been approved for other purposes, to treat those suffering from chronic pain," says Dr. Marbaldi. "Since the safety of these compounds has already been proven in humans, clinical trials for the new use are possible in the near future."

"We are now able to search for additional molecules that can focus more precisely on the process we identified in the sensory nerve cells," Prof. Feinzylver elaborates. "Such targeted molecules may cause fewer side effects and be less addictive than the treatments currently on the market, and they may give us new tools to reduce the heavy social costs that chronic pain exacts from us."

Dr. Nicholas Paniotis, Dr. Stephanie Alber, Dr. Shahar Dagan, Dr. Natalia Okladnikov, Dr. Indrak Kopel, Agustina Di Physio, Didi-Andras Song, Dr. Yordan Zur, Dr. Marco Tranzio also participated in the study. , Dr. Ida Rischel and Dr. Dalia Gordon, all from the Department of Biomolecular Sciences at the Weizmann Institute of Science; as well as Dr. Francisca Rother from the Max-Delbruck Center, Berlin and the University of Lübeck, Germany; and Dr. Prof. Eno Hartman from Lubeck University.