Researchers at the VIB-KU Leuven Center for Brain & Disease Research uncover how the upregulation of an ion channel called TRPM3 causes hypersensitivity in inflamed tissue. The new findings, published by professor Thomas Voets and his team in eLife, suggest new therapeutic avenues to help patients suffering from chronic pain.
Whenever you touch a hot pan, you withdraw your hand within a fraction of a second. Likely, you will also immediately feel a burning pain. This acute pain is actually a good thing – it functions as an alarm signal, warning you that high temperatures can cause dangerous and potentially life-threatening injuries. Sometimes this alarm system can become deregulated, for example upon tissue inflammation or injury. Nerve impulses can then be initiated at temperatures that are normally non-painful, and as a result, you may experience burning pain when taking a shower or walking in the sun, or, in the worst case, all the time. Researchers like Thomas Voets (VIB-KU Leuven) try to understand the mechanisms that underlie this type of hypersensitivity and how it may lead to chronic pain, in the hopes to ultimately find novel pain treatments for patients.
Temperature sensors and inflammation
Voets and his team have a particular interest in so-called TRP ion channels –proteins that allow the flow of charged ions across membranes to induce electrical signals. He explains why: “From earlier research, we knew that three such TRP ion channels act as the temperature sensors that initiate an acute pain response to heat. To better understand the mechanisms behind hypersensitivity, we wanted to know whether these three TRP channels, known as TRPM3, TRPA1 and TRPV1, become deregulated in inflamed tissue.”
The researchers used a mouse model to study local inflammation of the hind paw. “For one of the ion channels, TRPM3, we found differences in gene expression between the inflamed and the unaffected paw,” explains Marie Mulier, a PhD student in Thomas Voets’ lab and first author on the study. “TRPM3 expression was higher in the sensory neurons that innervate the inflamed hind paw compared to the other, unaffected paw.”
Reducing hypersensitivity
By measuring the activity of the sensory neurons, both in the fine endings in the skin and in their cell bodies close to the spinal cord, the researchers found that all three heat-activated TRP channels become hyperactivated in neurons that innervate the inflamed paw, explaining the increased heat sensitivity. But interestingly, a compound that inhibits the function of TRPM3 restored the sensitivity of the sensory neurons to normal levels.
“Our findings suggest that increased levels of TRPM3 in sensory neurons represent an important driver of inflammatory hypersensitivity to heat,” says Voets. “Therefore, drugs that dampen TRPM3 activity may become a viable therapy to reduce pain and hypersensitivity in patients.”