The current issue of Nature reports that scientists at SmithKline Beecham have demonstrated that a cell-surface protein that senses the pungent ingredient in chili peppers also plays a role in the sensation of pain and may be a useful target for pain-relieving drugs.
The protein is a cell-surface receptor found
predominantly on sensory neurons. The
receptor has been known for several years to
respond to heat as well as to capsaicin, the
component of chili peppers that induces a
burning sensation. Yet because this
understanding was based on experiments limited
to cells grown in the laboratory, the role of the
receptor in actual pain sensation in animals had
yet to be determined.
Scientists have taken the next
experimental step by studying not only cultured
cells but "knock-out" mice that had been genetically
altered to inactivate the capsaicin receptor, also
called the vanilloid receptor-1 (VR1).
As reported in Nature, the investigators used
electrophysiological tests to examine the effects
of various stimuli on isolated cells in culture. The
study found no specific responses to capsaicin
or heat in the cells from altered mice, in contrast
to the expected responses observed in cells from
normal mice. More relevant to drug discovery,
behavioral studies found that the altered mice
lacked altogether the enhanced sensitivity to
heat that normal mice show when tissue is
"The most intriguing finding is that the mice lost
the hypersensitivity to heat which is associated
with inflammation," said Dr. Frank S. Walsh, Vice
President and Director, Neuroscience Research,
SB. "This suggests that targeting VR1 may be
useful in treating pain resulting from tissue
injury, such as pain associated with surgery,
infection, ulcers, and cancer or its treatment."
Except in responding to certain stimuli, the mice
exhibited apparently normal behavior, as might
be expected given the prevalence of VR1 in
sensory neurones as contrasted with other cell
types. This observation gives an early
suggestion that a drug modifying VR1 may have
few side effects.
Another finding of the study indicated there
remains much to be learned about the molecular
basis of pain. Although the altered mice were
markedly less sensitive than normal mice to heat
in inflamed tissue, all the mice exhibited much
the same sensitivity to moderate heat when
inflammation was not present. The implication is that other receptors play a
role in sensing heat.
Years of investigation remain before this
work might lead to a novel painkiller. However, the findings are very interesting and give scientists a new direction to investigate.
Nature offers another example of
the usefulness of "knockout mice" in research
intended to yield new therapies. In such studies,
the gene encoding a protein of interest, in this
instance the gene encoding VR1, is inactivated.
The likely role of the protein can then be
determined by the effect of its absence.