Turning up the heat on pain research
An interview with Prof. Thomas Voets for Pain Awareness Month
September 12, 2023
Most of us are familiar with the painful, eye-watering sensation that comes with taking a bite out of a red hot chili pepper. But what puts the kick in these chilies?
Capsaicin is the active component of chili peppers, giving them their fiery taste. When you eat a hot pepper, capsaicin activates pain receptors in your mouth, which sends a message to your brain telling it you have eaten something spicy. In 2021, David Julius won a joint Nobel Prize for identifying the receptor involved: an ion channel named TRPV1 (pronounced “trip-vee-one”), one of 28 TRP channels in the human body.
As September is Pain Awareness Month, we caught up with Prof. Thomas Voets from the Laboratory of Ion Channel Research at the VIB-KU Leuven Center for Brain & Disease Research, who studies this TRP channel and others involved in pain processes. The lab's research offers potential future therapeutic outcomes for people experiencing chronic pain, the number one cause of disability and disease burden worldwide.
Hi Thomas, what are TRP channels exactly?
TRP channels are ion channels, molecular gateways in the membranes of cells: when they open, ions flow through the membrane, creating an electrical signal that activates cells. In sensory nerve cells, TRP channels sit at the nerve endings and open in response to changes in their environment, such as hot or cold temperatures, but also to chemical substances that evoke a hot or cold sensation, such as capsaicin from chili peppers or menthol from the mint plant. Activation results in an electrical signal that rapidly travels to the brain, which is interpreted as a feeling of, for example, cold or pain. As such, these TRP channels can be considered molecular thermometers or fire alarms.
Under pathological conditions, such as inflammation or injury, TRP channels can become deregulated: their expression increases, and they can become more sensitive. Consequently, a temperature that usually wouldn’t be painful might already excite the nerve, resulting in hypersensitivity and exaggerated pain responses.
How did you first get involved in pain research?
The main focus of the lab has always been ion channels. Pain is one of the key systems or processes in which TRP channels – a specific type of ion channel – are involved. Just over 10 years ago, we identified a particular TRP channel, TRPM3, that was not known to be involved in pain at the time. We were the first research group in the world to study this specific channel in the context of heat sensing and pathological pain, which enabled us to have a patent on screening the antagonist for this channel as a potential pain target. Excitingly, we will be testing the first compounds resulting from this research on humans later this year.
How do you study TRP channels involved in pain?
In our lab, we can study ion channels at different levels. We can do so-called patch-clamp recordings, where we measure the minuscule currents through TRP channels and investigate how their activity can be modulated or inhibited. We sometimes use animal models to understand more about the connection between TRP channels and pain. For example, we found out that the TRPM3 channel is associated with inflammation-induced pain through research in mice lacking this particular channel. Animal models can tell us many things about pain responses, but this method has its limitations.
For this reason, we also work closely with the clinic. In particular, we’ve been collaborating with Wouter Everaerts at UZ Hospital Leuven for several years. This partnership allows us to link the basic research conducted in our lab to clinical pathophysiology observed in patients suffering from painful bladder disorders.
Tell me more about your translational efforts in developing new drugs to combat pain-related disorders.
Many of the existing drugs available against pain have negative effects on the central nervous system. For instance, opioids are very powerful painkillers but are associated with addiction and sedation and can cause fatal overdoses. With our research, we aim to develop safer painkillers that tackle pain at the root, namely in the sensory nerves, and do not need to enter the brain.
Over a decade ago, after our initial discovery that TRPM3 plays a crucial role in pain signaling, we developed a screen to test over 40,000 compounds in collaboration with the Center for Drug Design and Discovery (CD3) in Leuven. From this screen, we were able to develop compounds that can specifically inhibit TRPM3 in sensory nerve cells and found that these compounds can potently inhibit pain in animal models of inflammation and nerve injury. Last year, we teamed up with Biohaven Pharmaceuticals in New Haven, Connecticut, who will test the first of these TRPM3 antagonists, dubbed BHV-2100, in a Phase I study in healthy human volunteers later this year.
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