article
Scripps research team sheds light on long-sought cold sensation gene
Contact: Marisela Chevez
mchevez@scripps.edu
858-784-2171
Scripps Research Institute
Discovery could lead to new treatments to ease pain
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.
###
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.
Contact: Marisela Chevez
mchevez@scripps.edu
858-784-2171
Scripps Research Institute
Discovery could lead to new treatments to ease pain
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.
###
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.