Detecting Cold, Feeling Pain: Study Reveals Why Mentho - 芳療

http://www.sciencedaily.com/releases/2007/05/070530132405.htm
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Detecting Cold, Feeling Pain: Study Reveals Why Menthol Feels Fresh

Science Daily — Scientists have identified the receptor in cells of the
peripheral nervous system that is most responsible for the body's ability to
sense cold.


The finding, reported on-line in the journal "Nature" (May 30, 2007), reveals
one of the key mechanisms by which the body detects temperature sensation.
But in so doing it also illuminates a mechanism that mediates how the body
experiences intense stimuli -- temperature, in this case -- that can cause
pain.


As such, the receptor -- known as menthol receptor TRPM8 -- provides a target
for studying acute and chronic pain, as can result from inflammatory or nerve
injury, the researchers say, and a potential new target for treating pain.

"By understanding how sensory receptors work, how thresholds for temperature
are determined, we gain insight into how these thresholds change in the
setting of injury, such as inflammatory and nerve injury, and how these
changes may contribute to chronic pain," says senior author David Julius,
PhD, chairman and professor of physiology at UCSF.

The menthol receptor, and other temperature receptors discovered in recent
years by the Julius lab, offer potential targets for developing analgesic
drugs that act in the peripheral, nervous system, rather than centrally,
where opiate receptors act, he says.

The finding is a milestone in an investigation the team began several years
ago. In 2002, the researchers discovered that the receptor was activated by
chemical cooling agents such as menthol, a natural product of mint, and cool
air. They reported their discovery, or "cloning," of the receptor in "Nature"
(March 7, 2002), hypothesizing that the receptor would play a key role in
sensing cold. However, some subsequent papers questioned this theory.

In the current study, the team confirmed their hypothesis by "knocking out"
the gene that synthesizes the receptor, both in sensory neurons in cell
culture and in mice. The cells in culture were unresponsive to cooling
agents, including menthol. The genetically engineered mice did not
discriminate between warm and cold surfaces until the temperature dropped to
extremes.

"It's been known for years that menthol and related cooling agents evoke the
psychophysical sensation of cold -- somehow by interacting with the aspect of
the sensory nervous system that's related to cold detection," says Julius.

The current study, he says -- led by Diana M. Bautista, PhD, and Jan Siemens,
PhD, of the Julius lab and Joshua M. Glazer, PhD, of the lab of co-senior
author Cheryl Stucky, PhD, of the Medical College of Wisconsin -- puts that
question to rest.

As the mice lacking the gene were not completely insensitive to cold -- they
avoided contact with surfaces below 10 degrees C, though with reduced
efficiency -- the next step, says Julius, will be to illuminate this residual
aspect of cold sensation.

The finding is the latest of a series of discoveries led by the Julius lab on
the molecular mechanisms of temperature sensation and pain. In 1997, the lab
cloned the gene for the capsaicin receptor, the main pungent ingredient in
some chili peppers (Nature, Oct. 23, 1997), and in 2000 reported that, in
mice, the receptor triggers the nerves to fire pain signals when they are
exposed to high ambient heat or the fiery properties of peppery food.
(Science, April 14, 2000). The study demonstrated that capsaicin and noxious
heat elicit the sensation of burning pain through activation of the same
receptor on sensory neurons.

Most recently, they identified the receptor of isothiocyanate compounds,
which constitute the pungent ingredients in such plants as wasabi and yellow
mustard. In response to high temperatures, the receptor produces pain and
irritation.

"All of these studies use natural products to understand pain mechanisms in
the periphery of the body, where they are first sensed," says Julius.

Ultimately, pain signals are transmitted from the peripheral nervous system
into the body's central nervous system -- moving through nerves in the spinal
cord and brain stem up to the brain, which prompts a response, or "feeling."
Co-author of the current study Allan Basbaum, PhD, also of UCSF, is a pioneer
of research into the mechanism of chronic pain within the central nervous
system.

The Julius team's complementary work is focused at the level of the sensory
nerve fiber, where the signals are first initiated. "We want to know," Julius
says, "how do you detect these stimuli to begin with" How do your sensory
nerve endings do this to begin with" And what are the biochemical and
biophysical mechanisms that account for this""

All three receptors the Julius lab has discovered are members of the TRP
family of ion channels expressed on sensory neurons. The latest finding adds
to the evidence, says Julius, that TRP channels are the principal transducers
of thermal stimuli in the mammalian periphery nervous system.

Other co-authors of the study were Pamela R. Tsuruda, PhD, of UCSF, and
Sven-Eric Jordt, PhD, of Yale University School of Medicine.

The study was funded by the National Institutes of Health, the Burroughs
Welcome Fund and the Human Frontiers Science Program Organization.

Note: This story has been adapted from a news release issued by University of
California - San Francisco

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