Leuven researchers uncover ion channel trio that mediates painful heat sensing

March 14, 2018

Researchers at VIB & KU Leuven have uncovered a trio of complementary ion channels in sensory neurons that mediate detection of acute, harmful heat. Having three redundant molecular heat-sensing mechanisms provides a powerful fail-safe mechanism that protects against burn injuries. The seminal findings have been published today in Nature.

Although the sensory neurons involved in acute pain signaling in mammals were described more than a century ago, the molecular mechanisms whereby these neurons detect harmful signals have remained largely unresolved.

A research team jointly led by prof. Thomas Voets (VIB - KU Leuven) and prof. Joris Vriens (KU Leuven) used genetic knockout models to pinpoint which molecular partners are involved. "We already knew several potential molecular heat sensors, but none of them, when deactivated, resulted in severe loss of acute noxious heat sensing," explains Ine Vandewauw, postdoctoral scientist in the lab of Thomas Voets.

The researchers started by eliminating two different heat-activated TRP ion channels, including one known to be also activated by capsaicin, the active component of chili peppers. But this only resulted in very mild deficits in heat sensing. Interestingly, most residual heat-sensitive neurons in the double knockout mice also responded to allyl isothiocyanate, responsible for the pungent sensation of mustard, radish and wasabi.

This chemical selectively activates a third TRP channel, which prompted the scientists to go one step further and generate a triple knockout. Mice with all three TRP channels eliminated showed a complete loss of heat-induced pain responses. Reintroduction of the receptors via transient transfection restored sensitivity to heat, and conversely, heat responses could also be suppressed by an inhibitor cocktail for all three TRP channels. The signaling was specific for the pain response to heat, as the animals responded normally to other painful stimuli such as cold, pressure or pinpricks, and their overall thermal preference was not affected.

This triple knock out mouse represents the first demonstration in mammals of elimination of the pain response to a physical stimulus at the level of the signal-transducing ion channel.

"Acute pain in response to heat is a crucial alarm signal in all mammals," explains Thomas Voets. "The presence of three redundant molecular heat-sensing mechanisms with overlapping expression in pain-sensing neurons creates a powerful fail-safe mechanism. It ensures we avoid dangerous heat, even if one or even two heat sensors are compromised."

In a next step, the researchers want to investigate how these channels can be targeted to treat chronic pain. Thomas Voets: "Millions of people worldwide suffer from ongoing, burning pain caused for instance by nerve damage or inflammation, and the currently available drugs to treat chronic pain often don't work well or cause addiction. In such conditions, the three heat-activated TRP channels can get deregulated, signaling painful heat even when there is no risk of burning. By developing new drugs that specifically temper the activity of these molecular heat detectors, we hope to be able to provide effective and safe means to treat chronic pain in patients."
-end-
Note: The lab of Thomas Voets is part of the VIB-KU Leuven Center for Brain & Disease Research and of the KU Leuven Department of Cellular and Molecular Medicine. The lab of Joris Vriens is part of the KU Leuven Department of Development and Regeneration

Publication

A TRP channel trio mediates acute noxious heat sensing, Vandewauw et al., 2018 Nature

Questions from patients

A breakthrough in research is not the same as a breakthrough in medicine. The realizations of VIB researchers can form the basis of new therapies, but the development path still takes years. This can raise a lot of questions. That is why we ask you to please refer questions in your report or article to the email address that VIB makes available for this purpose: patienteninfo@vib.be. Everyone can submit questions concerning this and other medically-oriented research directly to VIB via this address.

VIB (the Flanders Institute for Biotechnology)

Related Pain Articles from Brightsurf:

Pain researchers get a common language to describe pain
Pain researchers around the world have agreed to classify pain in the mouth, jaw and face according to the same system.

It's not just a pain in the head -- facial pain can be a symptom of headaches too
A new study finds that up to 10% of people with headaches also have facial pain.

New opioid speeds up recovery without increasing pain sensitivity or risk of chronic pain
A new type of non-addictive opioid developed by researchers at Tulane University and the Southeast Louisiana Veterans Health Care System accelerates recovery time from pain compared to morphine without increasing pain sensitivity, according to a new study published in the Journal of Neuroinflammation.

The insular cortex processes pain and drives learning from pain
Neuroscientists at EPFL have discovered an area of the brain, the insular cortex, that processes painful experiences and thereby drives learning from aversive events.

Pain, pain go away: new tools improve students' experience of school-based vaccines
Researchers at the University of Toronto and The Hospital for Sick Children (SickKids) have teamed up with educators, public health practitioners and grade seven students in Ontario to develop and implement a new approach to delivering school-based vaccines that improves student experience.

Pain sensitization increases risk of persistent knee pain
Becoming more sensitive to pain, or pain sensitization, is an important risk factor for developing persistent knee pain in osteoarthritis (OA), according to a new study by researchers from the Université de Montréal (UdeM) School of Rehabilitation and Hôpital Maisonneuve Rosemont Research Centre (CRHMR) in collaboration with researchers at Boston University School of Medicine (BUSM).

Becoming more sensitive to pain increases the risk of knee pain not going away
A new study by researchers in Montreal and Boston looks at the role that pain plays in osteoarthritis, a disease that affects over 300 million adults worldwide.

Pain disruption therapy treats source of chronic back pain
People with treatment-resistant back pain may get significant and lasting relief with dorsal root ganglion (DRG) stimulation therapy, an innovative treatment that short-circuits pain, suggests a study presented at the ANESTHESIOLOGY® 2018 annual meeting.

Sugar pills relieve pain for chronic pain patients
Someday doctors may prescribe sugar pills for certain chronic pain patients based on their brain anatomy and psychology.

Peripheral nerve block provides some with long-lasting pain relief for severe facial pain
A new study has shown that use of peripheral nerve blocks in the treatment of Trigeminal Neuralgia (TGN) may produce long-term pain relief.

Read More: Pain News and Pain Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.