not to move a broken arm, giving the
bone time to heal.
But when physical injury, metabolic
disorders such as diabetes, autoimmune
diseases or viral infections assault nerve
cells, pain is no longer protective. Nerves
can become trigger-happy, set off by
something as mild as the touch of bed-sheets. An estimated 20 million people
in the United States experience this kind
of pathological pain in their extremities.
“There are a lot of people suffering,
and it is really terrible for patients,” says
Catharina Faber of Maastricht University Medical Center in the Netherlands.
When examining a patient with such
pain, Faber and her colleagues first look
for an underlying condition that might
have attacked the patient’s nerves. In
many cases, there’s no obvious cause.
Research now suggests that genetic
changes that alter Nav1.7 may be a culprit. The seven SCN9A mutations
linked to small fiber neuropathy in
a study earlier this year appeared to
explain the peripheral pain of nearly
30 percent of study participants. This
study — reported by Faber, Maastricht
colleague Ingemar Merkies and other
collaborators in the Annals of Neurology
—and other recent studies suggest
that much of how pain is experienced
is inherited. Many scientists now
believe that genetic changes altering
Nav1.7, as well as other channels, may be
behind a lot of chronic, pathological and
mysterious pain.
Disorderly conduct
Stephen Waxman, who directs the Yale
Center for Neuroscience and Regen-
eration Research and is a biomedical
researcher with the U. S. Veterans Affairs
health care system, has been investigat-
ing Nav1.7 and its defects for more than
a decade. Working with Faber, Merkies
and others from around the world,
researchers in Waxman’s lab have iden-
tified more than two dozen mutations
in SCN9A. One, reported in Brain in
February, not only causes burning pain
in the extremities, but may also influ-
ence development of the hands and
feet. The many months of cell studies
required to fully understand how each
mutation influences Nav1.7’s construc-
tion and operation have been carried out
for about half.
Cellular close-up An important gateway for sodium ions, called Nav1.7, sits on nerve cells
that stretch from the body’s periphery all the way to the spinal cord. With enough stimuli at one
end, the Nav1.7 channel opens, passing along a message of pain to the spinal cord and brain.
Neurotransmitter
Painful
stimuli
Nav1.7 opens
Cell membrane
Stimuli
threshold
reached
Pain
message
travels
along axon
Body’s periphery
Spinal cord
additional mutations with the same effect
have since been discovered worldwide.
These genetic studies cemented
Nav1.7’s prominent role in human pain
perception. They also offered an unusual
treat: Rarely do geneticists find a tidy
and direct link connecting changes in
a single gene with what scientists call
a loss of function and its counterpart,
a gain of function. Often the picture is
much more complicated, with many
genes contributing to a trait or disease.
Yet SCN9A offered a textbook example: A single mutation in a single gene
could cause a person to lose the ability
to sense pain, while another mutation in
that same gene could amp up that ability,
making people feel pain even when they
should not.
“The genetic demonstration was very
clear. It was so clean. It’s usually not that
clean,” says Simon Halegoua, director of
the Center for Nervous System Disor-
ders at Stony Brook University in New
York. “That’s when multiple drug com-
panies jumped on it.”
Halegoua saw Nav1.7’s potential ear-
lier. In 1997, he and colleagues published
research describing a sodium channel
found predominantly in the peripheral
nervous system. Since it was the first
such sodium channel, the researchers
called it peripheral nerve type 1. Later,
it became known as Nav1.7 (Na for
sodium and v for voltage-gated chan-
nel). Earlier studies in rats and human
cells had hinted that some sodium chan-
nels favored certain body regions over
others. Some did their stuff primarily in
heart muscle, for example, and others
acted mainly in the brain. But this was
the first description of a sodium chan-
nel used mostly by peripheral nerves, at
the front line of the body’s interactions
with the world.
“That was the breakthrough,” says
Halegoua. “It opened the door to an
approach which would target those
peripheral pain-sensing neurons specifically. It was a paradigm shift in the way of
thinking about how to target pain. Instead
of targeting it at the brain like opiates do,
you would target it at the source —the
first nerve that gets excited.”
E. FELICIANO
www.sciencenews.org
