efforts,” says Stuart Mazzone of the Uni-
versity of Queensland’s St. Lucia campus
in Australia. “I think for a long time it
was in the ‘too hard’ basket. People just
gave up.”
That is, until some accidental victories.
A hot field
One of the early milestones in the
search for new treatments came in the
late 1990s, when researchers from the
University of California, San Francisco
announced the first discovery of a receptor that later turned out to have a role
in generating a cough. Receptors are
proteins that poke out from the surface
of cells like icebergs, waiting for a molecule that will attach to them and set off
a whole chain of events within the cell.
A substance that can trigger a
cough — an irritant like smoke or a hot
pepper — locks on to receptors on nerve
cells after getting sucked into the airway.
The joining of molecule to receptor then
activates nerves that run from the respiratory system to the brain stem. Nerves
in the brain stem alert nerves connecting
to muscles in the chest to immediately
contract. (Exactly how a cold makes you
cough is still not clear, but it probably
also has something to do with the irritation of nerve fibers.)
The California researchers who
described the new cough receptor, called
TRPV1, were not pursuing a cough mol-
ecule, but were instead interested in
chili peppers. The compound capsaicin,
which gives peppers their punch, is well
known for its array of potent neurologi-
cal effects: sweating, racing heartbeat,
pain — and coughing. Research teams
had been searching for the receptor
that could single-handedly release such
potent reactions, with the idea that it
could be an attractive target for pain
treatment and other problems.
Cough causes
Cough can often be relieved by
treating the underlying cause,
of which there are many. In some
cases, though, a cough lingers for
no apparent reason.
Smoking can irritate the airways and
cause cough. other irritants include air
pollution, perfumes or allergens.
Asthma can cause a cough that
becomes worse when a person is
exposed to other irritants or cold air.
Gastroesophageal reflux disease
occurs when stomach acids flow into
the esophagus. these acids can
trigger cough receptors.
Infections including flu, pneumonia,
the common cold and whooping cough
can produce a cough that sometimes
lingers.
Heart failure can lead to fluid buildup
in the lungs, causing chronic cough.
Receptor relief Various receptor molecules that play a role in regulating body temperature have
received attention as potential off switches for cough. these receptors are triggered by a range of
stimulants (some listed), but blocking temperature sensing along with cough may prove problematic.
Receptor
Natural stimulant
trpa1
mustard oil, mint
trpm8
Cinnamon, mint
trpV1
Chocolate, chili
sourCe: m. G. belVIsI E T AL/CHES T 2011
soothing feeling of the menthol aids
smoking and addiction.)
But the relief from TRPM8 activation
is temporary; menthols quickly disappear
from the body. What’s more, activating
the receptor won’t relieve chronic cough.
TRPV1 would be a good candidate but
has proved problematic. Without that
receptor, the body has trouble regulat-
ing its own temperature, or detecting the
temperature of outside substances. Vol-
unteers in clinical trials were inclined
to perceive the temperature of very hot
liquids (such as bathwater at 120º Fahr-
enheit) as “optimal.” Reporting on initial
tests of a TRPV1 blocker last year in the
journal Pain, an international research
team noted that, “it is not possible to
know whether or not the observed
changes in core body temperature, heat
pain threshold and perception of hot
liquids foretell a significant clinical risk
of fever or burns.”
The success of using TRPV1 inhibitors
depends on the ability to overcome the
side effects of impaired thermoregula-
tion while still blocking cough or pain,
Canning says. “Quite frankly, I think a lot
of companies got scared off.”
Enthusiasm for TRPV1 may be cool-
ing, but interest in other receptors,
