Rare Mutations Give Clues to Understanding Common Pain Conditions

Genetics

A new study builds the case for ion channel proteins as contributors to pain. Image: DNA double helix. Credit: idrutu/123RF Stock Photo.

Some neuropathic pain conditions—the type caused by damage to nerves—have known causes. For example, diabetes, chemotherapeutic treatment for cancer, and traumatic injury can all produce nerve damage that leads to neuropathic pain. But many cases arise inexplicably, either at a young age or later in life. In the past decade, researchers have identified the genetic roots of some of these mysterious pain conditions in families with rare inherited disorders. Those findings have provided clues about more common pain conditions, and about the interactions between pain and temperature.

In a new study published in the journal Nature Communications, researchers in Germany now describe a new mutation in a family with a mysterious inherited condition in which painful episodes were brought on by exposure to the cold. The research adds to the evidence that a protein called Nav1.9 plays a key role in sensing pain, and cold-evoked pain in particular.

The “Nav” in Nav1.9 stands for voltage-gated sodium channel, a family of tiny, barrel-shaped proteins that sit in the cell membrane and give neurons their electrical excitability—the basis for neural communication. All so-called excitable cells, including neurons in the brain, muscle and heart, contain some of the nine known members of the Nav family. The anesthetic lidocaine blocks pain—and all other touch sensations—by blocking Nav channels and silencing neurons. But the trick to using Nav channels as therapeutic targets for pain—which researchers and pharmaceutical companies are keen to do—is to block Nav channels that are found only in pain-sensing neurons while leaving other excitable cells in working order.

Researchers made a breakthrough in 2006 with the discovery of a mutation in people with an extremely rare condition called congenital insensitivity to pain (CIP). People with CIP often suffer extreme injuries and even death because they are unable to feel pain. Some patients with CIP had a mutation in the gene for another sodium channel, Nav1.7, which rendered them insensitive to pain but left other senses intact. Since then, several research groups have continued to find mutations in Nav1.7, Nav1.9 and the related Nav1.8 in patients with both rare and more common neuropathic pain conditions, which is informing their understanding of how each channel contributes to the sensation of pain.

The newly described mutation in Nav1.9 made the sodium channels hyperexcitable, which causes peripheral nerves to send increased pain signals to the spinal cord and brain. While cooling nerves usually slows their activity, the hyperexcitability caused by the mutation was sustained at cool temperature, which the researchers suspect might be tied to the patients’ cold sensitivity.

Illustrative of the complexity of pain signaling and its relation to temperature, in another neuropathic pain condition called erythromelalgia, caused by a mutation in Nav1.7, painful episodes are brought on by heat or exercise and soothed—rather than worsened as in the new study of Nav1.9—by cooling the skin. In 2013, a research group in Taiwan found that hyperexcitability in Nav1.7 caused by the mutation was heightened at elevated temperature.

Nav1.9 has been shown in other research to be important for cold-evoked pain, but the channel does not “sense” cold on its own; rather it may interact with other molecules that do so. Another class of ion channels called transient receptor potential channels (TRPs) are capable of sensing temperature. For example, the TRPV1 channel opens in response to painful heat and to capsaicin, the pungent chemical in chili peppers. Meanwhile, the TRPM8 channel responds to cold temperature and menthol. Researchers believe that more cold-sensing molecules remain to be discovered. —Stephani Sutherland

To read about the new research in more detail, see the related Pain Research Forum news story here.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance journalist in Southern California. Find her at StephaniSutherland.com or on Twitter @SutherlandPhD