in the transmission of pain messages from noci-
ceptive neurons to the spinal cord. The protein,
christened Nav1.7, sits on the surface of the neu-
ron and serves as a channel for sodium ions to
pass into the cell, which enables electrical
impulses constituting the pain signal to propa-
gate along the threadlike axon that connects to
another neuron in the spinal cord.
The mutations the researchers discovered in
the SCN9A gene yield malformed versions of the
Nav1.7 protein that don’t allow sodium ions to
pass into nociceptive neurons. With their noci-
ceptors incapable of conducting pain signals, the
children were oblivious when they chewed their
tongues or scalded themselves. “The beauty
of working with these extremely rare families
is that you can identify single genes which
have the mutation and essentially are human-
validated analgesic drug targets,” Cox says.
Mutations in the SCN9A gene are also linked
to a rare condition called inherited erythromel-
algia, or man-on-fire syndrome. Patients who
speaks animatedly and possesses a cheery dispo-
sition despite having made pain his life’s work.
He and his colleagues found, as another group
had, that man-on-fire patients had mutations
in their SCN9A gene. Those mutations have the
opposite effect of the one in the pain-free kids
from Pakistan, creating Nav1.7 channels that
open too easily, allowing sodium ions to flood
in even when they shouldn’t.
Through lab experiments conducted on neu-
rons in petri dishes, Waxman and his colleagues
proved that this was the mechanism by which
the SCN9A mutations caused the syndrome in
patients like Costa. “We were able to put the
channel into pain-signaling neurons and cause
them to go BRRRP! when they should be going
bop-bop,” says Waxman, referring to the hyper-
activity that results from the unabated inflow
of sodium ions. In patients with the syndrome,
this defect causes nociceptors to bombard the
brain with pain messages constantly.
The discovery that Nav1.7 can open or close‘I see people in pain, and I see the grimace, the strain on their faces,
and the stress, and I have none of that.’
Jo Cameron, a patient with a genetic insensitivity to painhave it face the extreme opposite of insensitivity
to pain: a burning sensation on their hands, feet,
and face. In warm surroundings, or with slight
exertion, the sensation gets unbearably intense,
akin to holding one’s hand over a flame.
Pamela Costa, a 53-year-old clinical psycholo-
gist from Tacoma, Washington, who suffers from
the syndrome, describes the pain as “inescap-
able.” To cope, she has her office temperature
set at a chilly 60 degrees. She can sleep only with
a complement of four fans around her bed and
the air-conditioning on at full blast. In an ironic
similarity to individuals with pain insensitivity,
the constant burning sometimes makes it hard
for Costa to discern hot surfaces, which is how
she burned her arm a year ago while ironing.
“I didn’t realize until I heard a hissing sound
from my skin getting seared,” she says. “It was
the same sensation as I was already having.”
Stephen Waxman, a neurologist at Yale Uni-
versity School of Medicine and one of the world’s
foremost experts on nerve conduction, has stud-
ied Costa and others like her in his lab at the
Veterans Affairs Medical Center in New Haven,
Connecticut. Gracious and affable, Waxman
the floodgates to nociceptive pain signals
has made the channel an attractive target
for researchers looking to develop new pain
medications that don’t pose the risk of addic-
tion that opioids do. Opioids work by binding to
a protein on the surface of nerve cells called the
mu-opioid receptor, causing the receptor to com-
municate with proteins inside the cell. While
the action of some of these proteins alleviates
pain, the receptor’s communication with other
proteins results in pleasurable feelings. The
body develops a tolerance to these drugs, mean-
ing that higher and higher doses are required
to trigger the sense of euphoria, which can
cause addiction.
Because Nav1.7 is present only in damage-
sensing neurons, a drug that selectively turns
off the channel promises to be an effective pain
reliever. The sole known side effect is the loss
of the sense of smell. Likewise, individuals with
the mutation also can’t smell. Existing local
anesthetic drugs such as lidocaine indiscrimi-
nately block nine sodium channels in the body,
including ones that are key to an array of brain
functions, which is why doctors must limit theirA WORLD OF PAIN 63