Get peace of mind by targeting chronic pain gateways

Some one-fourth of the world’s population suffers from chronic pain at some point in their lives. In contrast to acute pain (the sensation after hitting a finger with a hammer, for example), chronic pain has no apparent cause and can last for years or a lifetime. Chronic pain burdens include damage to mental and physical health, decreased productivity, and drug addiction. A new study, led by scientists at the Weizmann Institute of Science, uniquely treats this pain by targeting a major gateway that leads to activation of genes in peripheral nerve cells that play a role in many forms of chronic pain. Suggests an approach. Results of this study were announced today Science..

Pain begins with sensory neurons, which pass information from the skin to the central nervous system. Damage, chronic damage, or illness to these neurons can “short-circuit” them and send a continuous pain message. Mike Finesilver Professor Members of the Institute’s Department of Biomolecular Science are investigating the molecules that regulate biomolecular messaging activity within these neurons. Found in all cells, these molecules (importins) act as a conduit between the cell nucleus and its cytoplasm, allowing molecules to enter and exit the nucleus and control access to genes. This role is of special importance in peripheral neurons, a long, thin body that can take several hours for a molecular message to reach the cell nucleus from nerve endings. Several key Fein Gimbers and his team, for example, relayed messages about damage to nerve cell bodies and initiated repair mechanisms.

To ask whether infantin is involved in chronic neuropathic pain, researchers led by Dr. Letizia Marvaldi of Fainzilber’s group began by investigating a large number of importin-mutant mice generated in his lab. We started to screen the strains. Michael vader At the Maxdelbrook Center in Berlin, which helped with this research. The research was supported by the European Research Council.

Blocking the activity of importin alpha-3 may be particularly suitable for preventing persistent chronic pain

Behavioral screening of these different strains revealed a specific importin (importin alpha-3) as the only importin involved in the control of pain pathways. Next, the team sought to identify a gene expression pattern associated with long-term pain in peripheral neurons and how it was associated with importin alpha-3 activity. Analyzing the difference in expression patterns between normal neurons and those lacking importin alfa 3, Dr. Malvardi turned his attention to c-Fos, a protein that importin alfa 3 brings to the nucleus. c-Fos is a transcription factor, a molecule that increases or decreases the expression of many genes. Further experiments in mice have shown that c-Fos accumulates in the nucleus of peripheral nerve cells in mice suffering from chronic pain.

Next, we used a specialized virus as a tool to reduce or abolish mouse peripheral nerve importin α-3 or c-Fos. These mice had significantly less response to chronic pain conditions than normal mice. Further studies have shown that importin alpha-3 is important for late and chronic pain. c-Fos is also involved in the early pain response, but seems to enter the nucleus by other means in the early stages. This suggests that blockade of importin α-3 activity may be particularly suitable for the prevention of persistent chronic pain.

The research team then took that finding to the next level and asked how easily it could be translated into clinical applications. They used a special database called Connectivity Map (CMap) provided by Broad Institute of Massachusetts. This reveals a link between drugs and gene expression patterns. This database allowed us to identify approximately 30 existing drugs that could target the importin α-3-c-Fos pathway. Almost two-thirds of the compounds they identified were previously unknown to be associated with analgesia. The team chose two – one for cardiotonics and another for antibiotics – retested with mice. In fact, injection of these compounds alleviates neuropathic pain symptoms in mice.

“The compounds identified in this database search are a sort of fast track. Evidence that drugs already approved for other uses in patients could probably be diverted to treat chronic pain,” Marvaldi said. I will. “These compounds have already been shown to be safe in humans and may be in clinical trials in the near future.”

“We are now in a position to screen new and better drug molecules that can accurately target this chain of events in sensory neurons,” said Finesilber. “Such target molecules have fewer side effects than current therapies, may be less addictive, and may offer new options for reducing the burden of chronic pain.” Nicolas Panayo Dr. Tis, Dr. Stephanie Albert, Dr. Shacher Y. Dagan, Dr. Natalia Okradnikov, Dr. Indrek Koppel, Agostina Dipisio, Didi Andreas Song, Yardenstur, Marco Terenzio, Dr. Ida Rishal and Dr. Dalia Gordon, Everything in the Biomolecular Science Division of the Wiseman Institute of Science. Dr. Franzis Carroter of the Maxdelbrook Center in Berlin and the University of Lubeck in Germany. Professor Enno Hartmann of the University of Lubeck.

Professor Michael Fainzilber’s work is supported by the Moross Integrated Cancer Center. David Burton Center for Research on Life Chemistry. Nella and Leon Benoziyo Center for Neurological Disorders; Laraine and Alan Institute of Biological Mass Spectrometry, A. Fisher. Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. Rising Tide Foundation; Lawrence Faith; House of Florence and Charles Cuevas. Estate of Lily Flop; Estate of Lola Asseof; and Council of European Studies. Professor Finesilver chairs Professor Chaya of Molecular Neuroscience.