Putting the Winter in Wintergreen1

By Jason Socrates Bardi

"Fifty degrees below zero stood for a bite of frost that hurt..."

—Jack London, To Build a Fire, 1908

In Jack London's famous story about a frostbitten trek across the Yukon, the narrator describes a stinging feeling in his extremities before the numbness sets in and he loses sensation altogether. Beyond the simple wisdom of not traveling alone by foot in the Arctic, this story illustrates one of the strange things about the way that humans experience temperature—the sensation of cold can be perceived as burning pain.

In an article appearing in the journal Neuron this week, Scripps Research Institute Assistant Professor Ardem Patapoutian and this colleagues explore the relationship between cold and pain on the molecular level.

Our experience of temperature is determined by long, specialized neurons that connect to the brain through the spinal column. These neurons have nerve endings embedded in our skin, where they detect the temperature and communicate this information to the brain.

The nerve endings detect temperature with a class of temperature-detecting molecules on the nerve's surface known as the transient receptor potential (TRP) ion channels. Different ion channels in this family are activated within different temperature ranges, and the integration of these signals is the basis of our ability to sense temperature.

When a person's hand touches ice, for instance, the cold channels on the nerve endings open up, allowing an influx of positively charged calcium ions into the nerve cell. This influx causes a slight change in the electrical potential of the cell, and when enough channels are activated, the electrical signal causes the neuron to fire. This signal travels to the spinal cord and from there to particular brain regions, where it is integrated with others and interpreted as cold.

Last year, Patapoutian and his colleagues at Scripps Research and the Genomics Institute of the Novartis Research Foundation (GNF) identified and isolated the molecule TRPA1 (formerly known as ANKTM1), which is involved in this process. TRPA1 is inactive at room temperature and higher temperatures, and only becomes active at painful or "noxious" cold temperatures. Below 15 C (59 F), the TRPA1 channels become activated, open, and mediate the body's ability to sense cold through the skin. (Previously Patapoutian and his colleagues identified and cloned TRPV3, the first-known gene that makes skin cells able to sense warm temperatures, and TRPM8, which is the first cold-sensing molecule ever identified.)

Pain and the Ion Channels

The combination of pain and temperature sensation is a well-established one—as in Jack London's bite of frost that hurts. And it makes sense that there would be a connection. Extreme freezing or scorching hot temperatures can both be dangerous, and our survival may depend on our ability to sense them as painful stimuli and react accordingly.

But the combination is not clear on the molecular level. Some cold receptors communicate a sensation like cold when they are activated, and some communicate a feeling of pain.

Patapoutian and his colleagues wanted to know if TRPA1 is involved in pain sensation as well as cold sensation. To answer this, they looked for common chemical compounds that could activate the receptor.

In the latest issue of Neuron, the scientists describe how the active ingredients in cinnamon oil, wintergreen oil, clove oil, ginger, and mustard oil all turn on the noxious cold temperature receptor TRPA1. Two of these compounds, cinnamaldehyde from cinnamon oil and allyl isothiocyanate from mustard oil, were specific only to the noxious cold-sensing channel TRPA1 (and not other temperature-activated TRP channels).

This may seem odd, since our experience of these compounds (think wasabi and cinnamon gum) is one of burning and not cold. This, says Patapoutian, is because TRPA1 is more than just a cold receptor—when it is activated, it also communicates pain. As further proof of this, the scientists showed that TRPA1 is activated by an inflammatory peptide called bradykinin.

If TRPA1 is involved in inflammation and pain-mediation as this study suggests, TRPA1 may be an important therapeutic target. Significantly, TRPA1 is expressed in the same neurons as the ion channel TRPV1, which is known to be involved in inflammation and the communication of pain to the brain. Several compounds that block TRPV1's action are currently under investigation for chronic pain indications.

Since TRPA1 also seems to be involved in mediating pain, it, too, may be a target for pain therapeutics, and Patapoutian and his colleagues would like to use this information to find compounds that could become useful therapeutics.

To read the article, "Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin" by Michael Bandell, Gina M. Story, Sun Wook Hwang, Veena Viswanath, Samer R. Eid, Matt J. Petrus, Taryn J. Earley, and Ardem Patapoutian in the March 25, 2004 issue of the journal Neuron, see: http://www.neuron.org/


Send comments to: jasonb@scripps.edu



Cinnamaldehyde, the active ingredient in these cinnamon sticks, causes a burning sensation by activating the noxious cold-sensing channel TRPA1. Photo by Tom Gatz and Janet Hightower of Biomedical Graphics.