In experiments with mice, researchers have found that eliminating what
appears to be a master genetic switch for the development of pain-sensing
neurons knocks out the animals' response to "neuropathic
pain." Such pain is abnormal pain that outlasts the
injury and is associated with nerve and/or central nervous
system changes. The animals rendered deficient in the
gene, called Runx1, also showed lack of response to
discomfort caused by heat and cold and
inflammation. The researchers said that their findings,
reported in the February 2, 2006, issue of Neuron, could have implications
for the design of improved pain
therapies.
In
their experiments, Qiufu Ma and colleagues studied the Runx1 gene because
past research had shown it to code for a
protein "transcription factor," which is a master
regulator of multiple genes. Runx1 is one of a group of proteins that are
key players involved in transmitting external sensory information, like pain
and the perception of movement, to the spinal cord. In two other related
papers in the same issue, Silvia Arber and colleagues and Tom Jessell and
colleagues examine related aspects of the biological importance underlying
the Runx transcription factors.
Runx1 was known to be expressed
only in sensory nerve cells called "nociceptive" cells, involved in sensing
pain. Such pain-sensing cells function by translating painful stimuli into
nerve signals via specialized pores called "ion channels" in the neurons, as
well as specialized receptors. The researchers' studies of Runx1 in these
cells revealed that during embryonic development, the gene is
characteristically expressed in pain-receptor cells involved in neuropathic
pain. When they knocked out the gene, they found that the normal development
of such specialized nerve cells was impaired. The animals had lost ion
channels known to be involved in reacting to painful heat or cold, as well
as those involved in pain due to damaged tissue. The researchers also found
that the Runx1-deficient animals showed deficient wiring of certain types of
pain neurons.
In key experiments, the
researchers measured the Runx1-deficient animals' response to four types of
pain--thermal, mechanical, inflammatory, and neuropathic.
The researchers produced a pain
response by subjecting the animals' hindpaw to either the cold of acetone or
an uncomfortably warm plate (thermal); the uncomfortable prick of a filament
(mechanical); an injection of an inflammation-inducing chemical
(inflammatory); or nerve damage (neuropathic). They quantified the animals'
response by measuring how long the animals lifted or licked their affected
paw in response to the treatments.
Ma and his colleagues found that,
while the deficient animals showed normal response to mechanical pain, they
showed significantly lowered thermal, neuropathic, and inflammatory pain
response.
The researchers concluded that
while the diverse specialized components of the pain-sensing machinery could
be established in a piecemeal fashion, "Our data, however, provide strong
evidence that Runx1 is required to specify the receptive properties of a
large cohort of nociceptive sensory neurons." They also concluded that the
dual functions they discovered for Runx1--controlling specification of
sensory neurons and regulating how they target their wiring--"form a genetic
basis for the assembly of specific neural circuits for nociceptive
information processing.
"Finally, the identification of a
core transcriptional control program for many of the ion channels and
receptors known to transduce noxious stimuli has intriguing implications for
the design of more effective pain therapies," they wrote.
Chih-Li Chen, Yang Liu, Chuan Cen,
Omar Abdel Samad, and Qiufu Ma of the Dana-Farber Cancer Institute and
Harvard Medical School in Boston, MA; Daniel C. Broom and Clifford J. Woolf
of Massachusetts General Hospital and Harvard Medical School in Charlestown,
MA; Albert I. Chen, Joriene C. de Nooij and Thomas M. Jessell of Howard
Hughes Medical Institute and Columbia University in New York, NY; Zhe Li of
Dartmouth Medical School in Hanover, NH. Ina Kramer, Markus Sigrist, and
Silvia Arber of the University of Basel and Friedrich Miescher Institute in
Basel, Switzerland; Ichiro Taniuchi of Howard Hughes Medical Institute and
New York University School of Medicine in New York, NY.
This work was supported by grants
from the National Institutes of Health to Q.M. and C.J.W. C.C. is a fellow
of Charles King Medical foundation, J.C.D. is a fellow of Helen Hay Whitney
Foundation, and Q.M. is a Claudia Adams Barr Scholar and a Pew Scholar in
Biomedical Sciences. I.K., M.S., and S.A. were supported by a grant from the
Swiss National Science Foundation, by the Kanton of Basel-Stadt, and by the
Novartis Research Foundation. T.M.J. is supported by grants from the Human
Frontier Science Program, National Institutes of Health, the National
Institute of Neurological Disorders and Stroke, and The Leila and Harold
Mathers Foundation and is a Howard Hughes Medical Institute Investigator.
J.C.d.N. was a post-doctoral fellow of the Helen Hay Whitney Foundation.
Chen et al.: "Runx1 Determines
Nociceptive Sensory Neuron Phenotype and Is Required for Thermal and
Neuropathic Pain." Publishing in Neuron 49, 1-13, February 2, 2006. DOI
10.1016/j.neuron.2005.10.036.
Kramer et al.: "A Role for Runx
Transcription Factor Signaling in Dorsal Root Ganglion Sensory Neuron
Diversification." Publishing in Neuron 49, 1-15, February 2, 2006. DOI
10.1016/j.neuron.2006.01.008
Chen et al.: "Graded Activity of
Transcription Factor Runx3 Specifies the Laminar Termination Pattern of
Sensory Axons in the Developing Spinal Cord." Publishing in Neuron 49, 1-14,
February 2, 2006. DOI 10.1016/j.neuron.2005.12.028