Detecting Cold, Feeling Pain: Study Reveals Why Menthol Feels Fresh

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Detecting Cold, Feeling Pain: Study Reveals Why Menthol Feels Fresh

http://www.medicalnewstoday.com/medicalnews.php?newsid=72681

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 " , 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 Julius, PhD, chairman and professor of

physiology at UCSF.

The methanol 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 M. Bautista, PhD, and Jan

Siemens, PhD, of the Julius lab and 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.

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Other co-authors of the study were Pamela R. Tsuruda, PhD, of UCSF,

and Sven- 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.