Discovery Of Cold Sensation Gene Could Lead To New Treatments To Ease Pain

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Discovery Of Cold Sensation Gene Could Lead To New Treatments To

Ease Pain

http://www.medicalnewstoday.com/medicalnews.php?newsid=69749

The discovery, reported in the May 3 issue of the journal Neuron,

might one day lead to the development of drugs that induce cold

sensation as an analgesic, or block it to prevent certain forms of

chronic pain associated with cold sensation.

" This study represents the first demonstration that a single gene is

responsible for most cool temperature sensation, " says team leader

Ardem Patapoutian, who has joint appointments with the Department of

Cell Biology at Scripps Research and the Genomics Institute of the

Novartis Research Foundation. " Many previous candidates have been

postulated to play a role in our ability to sense cool temperatures,

but none have withstood the test of genetics, " he says.

TRPM8 was first discovered by Patapoutian's group and proposed as a

key gene controlling cold sensation. To test the hypothesis, the

group observed the behavior of mice genetically altered to lack the

gene in response to cold stimuli.

When placed in compartments with a temperature gradient, or in an

enclosure where they could choose between two temperatures, mice

without TRPM8 showed essentially no preference in the temperature

range of 18 to 31°C, suggesting their ability to sense this range

was completely disabled without the gene. Normal mice, on the other

hand, found cold temperature unpleasant, reliably avoiding cold

temperatures in favor of warmer areas.

" It's pretty amazing that one gene could impact thermal sensation

this much, " says Ajay Dhaka, a Scripps Research postdoctoral fellow

in the Patapoutian lab and lead author on the Neuron paper. " It

really highlights the importance of the peripheral nervous system

and how temperature affects our behavior, " he says.

The altered mice also showed little response to the application of

acetone to their hindpaw, which causes an unpleasant cold sensation,

while the acetone caused normal mice to flick their paw and lick

them.

TRPM8 codes for an ion channel found at the tips of sensory neurons,

which innervate the skin. When opened, ions flowing through TRPM8

lead to the activation of the sensory neuron, which in turn sends a

signal to the brain. The Patapoutian team's results support the idea

that activation of TRPM8 by temperature triggers cold

sensation. " TRPM8 acts as a gate, " says Dhaka, " At warm temperature

it remains closed, but opens when exposed to cool temperature. "

The TRPM8-deficient mice did not lose their ability to feel pain in

response to extreme cold, as evidenced by responses similar to wild

type mice when exposed to -1° C cold plates. This suggests that

other genes are responsible for this facet of cold sensation.

Though cold can be unpleasant or painful under certain

circumstances, it can also deaden pain, as illustrated by icing an

injury to relieve pain. To test this side of cold sensation, the

researchers injected the mice with small amounts of a pain-causing

chemical, formalin, and then exposed the affected paw area to a cold

plate.

Cold temperature clearly reduced the acute pain felt by control mice

as shown by a reduction in the response to formalin injection when

compared to the amount of time control mice spent flicking and

licking their paws when placed on a room temperature plate. In

contrast, TRPM8-deficient mice did not receive any acute pain relief

from the cold plate suggesting that cold activation of TRPM8 can

mediate some of the analgesic effects of cold.

Just how the same sensation can be interpreted as unpleasant under

certain circumstances and pleasant in others is still not clear, but

is a question the group plans to investigate. " It would be really

interesting to find out how the brain takes essentially the same

signal and, depending on context, interprets it differently, " says

Dhaka.

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Other authors on the paper, entitled " TRPM8 Is Required for Cold

Sensation in Mice, " were Amber Murray and Taryn Earley, from Scripps

Research, and Jayanti Mathur and Matt Petrus, from the Novartis

Research Foundation.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest

independent, non-profit biomedical research organizations, at the

forefront of basic biomedical science that seeks to comprehend the

most fundamental processes of life. Scripps Research is

internationally recognized for its discoveries in immunology,

molecular and cellular biology, chemistry, neurosciences,

autoimmune, cardiovascular, and infectious diseases, and synthetic

vaccine development. Established in its current configuration in

1961, it employs approximately 3,000 scientists, postdoctoral

fellows, scientific and other technicians, doctoral degree graduate

students, and administrative and technical support personnel.

Scripps Research is headquartered in La Jolla, California. It also

includes Scripps Florida, whose researchers focus on basic

biomedical science, drug discovery, and technology development.

Currently operating from temporary facilities in Jupiter, Scripps

Florida will move to its permanent campus in 2009.