The genetic study of a boy who is unable to feel pain has identified a protein that could be used for the development of a new generation of pain relievers against chronic pain.
From a physiological point of view, pain can be considered as an alarm signal intended to preserve the integrity of the body. For example, if your hand comes into contact with a burning object, the sensitive nerves present in this region will generate a nerve impulse which will first be sent to the spinal cord, to then be transmitted to the regions of the brain specialized in the processing of this information. Alerted by this message, the brain in turn sends a nerve impulse which takes the spinal cord in the opposite direction, reaching the muscles controlling the movements of the hand to dismiss it from the source of pain. This whole process is carried out in a fraction of a second, allowing to quickly put an end to a situation which would risk leading serious injuries if it persisted.
Absence of pain
This protection system, essential to survival, is however defaulting in certain neurological disorders such as congenital insensitivity to pain. As its name suggests, people with this very rare genetic disease (of the order of a person per million) can properly perceive all physical sensations (touch, pressure), but are nevertheless, from birth, completely insensitive to painful stimuli. In the absence of this protection signal, these people are therefore constantly at risk of injury (bites, burns, fractures) which, if they are not treated, can cause infirmities or serious infections that threaten their lives. The molecular mechanisms in question remain poorly understood, but mutations in a certain number of essential genes for the feeling of pain have been identified, the best characterized being that which prevents the production of a protein (called Nav1.7) in the sensitive nerves, which blocks the transmission of painful nerve influx.
New gene
According to new results obtained by a team of brilliant researchers from the University of Calgary, another protein, called USP5, could also play an important role in the transmission of the pain signal (1). In this study, the researchers analyzed in detail the entire genome of a child who died suddenly at the age of 16 and who was since his birth completely insensitive to pain.
This analysis revealed a unique mutation in a gene coding for the USP5 protein, an enzyme (deubiquitinase) known to control the activity of an ion channel (CAV3.2) which brings calcium inside the sensitive neurons and participates in the nerve implux associated with pain. Since this channel is identical to 99% to that found in mice, they created an equivalent mutation in these animals using the CRISPR publishing tool, a revolutionary technology (Nobel Prize in chemistry in 2020) which allows you to modify the sequence of any DNA very precisely.
They then observed that the mice whose protein USP5 had been transferred were less efficient to detect acute pain than normal mice and that they also developed resistance to inflammatory and chronic pain.
Chronic pain
These results suggest that the USP5 protein could be an interesting target for the development of a new type of pain relievers. This is particularly important in the context of chronic pain: remember that about 20% of the Canadian population is affected by persistent pain that disrupts daily activities and considerably decreases quality of life. This is a serious problem, because these pains are often resistant to the analgesics currently available, while those who have a stronger anti -darling action, such as opiates, can create dependence problems. Another important step in pain research has just been crossed.
(1) Antunes FTT et coll. A pathological missense mutation in the deubiquitinase USP5 leads to insensitivity to pain. J. Exp. With. 2025; 222: e20241877.
