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
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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.
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