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Molecule discovered to be key to pain
sensitivity
Gene variation identifies those with
higher pain threshold, lower risk of chronic pain
BOSTON - October 22, 2006 -Sensitivity to pain and the risk
of developing chronic pain appear to be influenced by levels of
a molecule known to be required for the production of major neurotransmitters.
In a report receiving early online release in the journal Nature
Medicine, an international research team based at Massachusetts
General Hospital (MGH) describes this unexpected role for the molecule
called BH4 and their findings that a particular set of variations
in a human gene involved in synthesizing the molecule appears to
reduce pain sensitivity.
"This is the first evidence of a genetic contribution to the
risk of developing neuropathic pain in humans. The pain-protective
gene sequence, which is carried by about 25 percent of the population,
appears to be a marker both for less pain sensitivity and a reduced
risk for chronic pain," says senior author Clifford Woolf,
MD, PhD, director of the Neural
Plasticity Research Group in the MGH Department of Anesthesia
and Critical Care. "Identifying those at greater risk of developing
chronic pain in response to medical procedures, trauma or diseases
could lead to new preventive strategies and potential treatments."
Previous studies in animals have shown that specific strains or
related groups of rodents have significant differences in their
risk of developing either neuropathic pain, which results from nerve
damage, or inflammatory pain, associated with the immune system's
response to injuries or conditions like arthritis. But except for
some rare inherited conditions, there has been no evidence that
genetics contributed to the risk of neuropathic pain in humans.
The research team had previously used gene chips to find that nerve
damage in rats altered the regulation of several hundred genes in
associated nerve cells. They began the current study by searching
through these genes to find any associated with common metabolic
pathways and found that three genes that increased expression in
response to nerve damage encoded enzymes involved in the production
and recycling of BH4, which is essential for the production of serotonin,
dopamine, norepinephrine and nitric oxide. Tests in rat models found
that the BH4-synthesizing enzymes were activated in injured sensory
neurons and that substances known to inhibit those enzymes reduced
pain, acting as analgesics. Directly injecting BH4 or a similar
molecule increased the animal's response to several painful stimuli.
As a result of the animal studies, the researchers hypothesized
that particular variations of human genes involved in the regulation
of BH4 might be associated with different responses to pain. Searching
for alterations in the gene for GCH1, the human version of the key
BH4-controlling enzyme, they genotyped tissues from 168 patients
who had participated in an earlier study of spinal disk surgery.
One specific GCH1 haplotype - a set of variations in the gene that
are inherited together- was more common in study participants who
reported less neuropathic pain in the year after their surgery.
To see if that haplotype had a similar association with other types
of pain, the researchers studied almost 400 healthy volunteers,
who participated in tests of their response to various slightly
painful experimental stimuli. Again, those participants with the
protective GCH1 haplotype - which the investigators showed reduces
the production of BH4 - also reported less pain, and volunteers
with two copies of the protective sequence were even less sensitive
to pain.
"Our results tell us that BH4 is a key pain-producing molecule
- when it goes up, patients experience pain, and if it is not elevated,
they will have less pain," says Woolf. "The data also
suggest that individuals who say they feel less pain are not just
stoics but genuinely have inherited a molecular machinery that reduces
their perception of pain. This difference results not from personality
or culture, but real differences in the biology of the sensory nervous
system.
"Now we need to identify what regulates the switching on of
BH4-controlling enzymes after nerve injury and how BH4 alters the
excitability of pain fibers. We also would like to see whether those
with the protective haplotype might participate more frequently
in potentially painful activities - such as extreme sports - or
if they have reduced levels of pain in arthritis and other common
conditions," he adds. Woolf is the Richard Kitz Professor of
Anaesthesia Research at Harvard Medical School.
The study was supported by grants from the U.S. National Institutes
of Health, the German Research Foundation, the German Federal Ministry
of Education and Research, and the Dr. Robert Pfleger Foundation.
Woolf is an advisor to and holds stock in Solace
Pharmaceuticals, a company that has licensed these findings
for potential drug development.
The co-first authors of the Nature Medicine report are Irmgard
Tegeder, MD, and Michael Costigan, PhD, of the MGH Department of
Anesthesia and Critical Care. Other co-authors are Robert Griffin,
Joachim Scholz, Andrew Allchorne, Alexander Binshtok, and Steven
Atlas of MGH; Andrea Abele, Helmut Schmidt, Corina Ehnert, Claudiu
Marian, Jan Adolph, Jorn Lotsch, and Gerd Geisslinger of the Institute
for Clinical Pharmacology, Frankfurt, Germany; Inna Belfer, Jemiel
Nejim, Tianxia Wu, David Goldman, and Mitchell Max, of the U.S.
National Institutes of Health; Luda Diatchenko, Swetha Sama and
William Maixner, University of North Carolina; William Carlezon
and Aram Parsegian, McLean Hospital, and Roger Fillingim, University
of Florida College of Dentistry.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, transplantation biology and photomedicine. MGH and Brigham
and Women's Hospital are founding members of Partners HealthCare
HealthCare System, a Boston-based integrated health care delivery
system.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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