Researchers suggest that mimicking a specific gene mutation that causes pain insensitivity could be one way to treat chronic pain.
In a study newly published in the journal Brain, researchers reveal how an Italian family with a mutation in a gene called Zinc finger homeobox 2 (ZFHX2) have a distinct tolerance to certain forms of pain.
“The members of this family,” says lead study author Dr. James Cox, of the Wolfson Institute for Biomedical Research at University College London in the United Kingdom, “can burn themselves or experience pain-free bone fractures without feeling any pain.”
“But they have a normal intraepidermal nerve fiber density,” he adds, “which means their nerves are all there, they’re just not working how they should be.”
“We’re working to gain a better understanding of exactly why they don’t feel much pain, to see if that could help us find new pain relief treatments,” Dr. Cox continues.
It is estimated that around 25.3 million adults in the United States are living with chronic pain, which is defined as pain that persists for at least 3 months. Such pain can limit a person’s mobility and interfere with day-to-day functioning.
Medications are available that may help individuals to manage chronic pain, such as non-steroidal anti-inflammatory drugs (NSAIDs) and — in more severe cases — opioids. However, these treatments are not always successful, and they can carry significant risks.
As such, there is a need to find new pain relief strategies. Researchers have been investigating congenital analgesia with the hope of uncovering some clues.
The genes behind pain insensitivity
Also referred to as congenital insensitivity to pain, congenital analgesia is a condition wherein an individual is unable to sense physical pain.
Mutations in the SCN9A gene are a known cause of congenital analgesia. SCN9A gene mutations prevent the formation of NaV1.7 channels, which are channels that transmit pain signals from the nerves to the brain.
Studies have investigated whether blocking NaV1.7 channels by targeting the SCN9A gene could yield new treatments for chronic pain, but they have yet to produce any effective medications.
Based on the results of their new study, Dr. Cox and team suggest a different approach to relieving chronic pain, which involves replicating a mutation in the ZFHX2 gene.
To reach their findings, the scientists used whole exome sequencing to analyze the DNA in blood samples taken from six members of an Italian family who have pain insensitivity.
Every member of this family cannot feel pain in response to noxious heat, capsaicin — the active component in chili peppers — or bone fractures. This very specific insensitivity to pain has been named Marsili syndrome by the researchers, after the name of the family.
Discovery may lead to new treatments
From their analysis, the researchers identified a novel mutation in the ZFHX2 gene that alters a section of its DNA sequence.
When the team bred mice to be absent of the ZFHX2 gene, they found that the pain threshold of the rodents changed.
The scientists then bred mice to possess the same ZFHX2 gene mutation found in the human blood samples. They found that this made the rodents insensitive to high temperatures.
On investigating these rodents further, the team found that the ZFHX2 gene controls other genes that are associated with pain signaling.
“With more research to understand exactly how the mutation impacts pain sensitivity, and to see what other genes might be involved, we could identify novel targets for drug development,” says study co-author Prof. Anna Maria Aloisi, of the University of Siena in Italy.
The authors suggest that one potential treatment to come from their findings could be gene therapy, in which the ZFHX2 gene mutation is mimicked.
“We hope that our findings and the subsequent research projects will help find better treatments for the millions of people worldwide who experience chronic pain and don’t get relief from existing drugs.”
First study author Dr. Abdella Habib, Qatar University, Qatar