|Gene Variation Affects Pain Sensitivity
and Risk of Chronic Pain
Finding May Lead to New Treatments
A new NIH-funded study shows that a specific gene variant in humans
affects both sensitivity to short-term (acute) pain in healthy
volunteers and the risk of developing chronic pain after one kind
of back surgery. Blocking increased activity of this gene after
nerve injury or inflammation in animals prevented development of
The gene in this study, GCH1, codes for an enzyme called
GTP cyclohydrolase. The study suggests that inhibiting GTP cyclohydrolase
activity might help to prevent or treat chronic pain, which affects
as many as 50 million people in the United States. Doctors also
may be able to screen people for the gene variant to predict their
risk of chronic post-surgical pain before they undergo surgery.
The results appear in the October 22, 2006, advance online publication
of Nature Medicine.1
"This is a completely new pathway that contributes to the development
of pain," says Clifford J. Woolf, M.D., of Massachusetts General
Hospital and Harvard Medical School in Boston, who led the research. "The
study shows that we inherit the extent to which we feel pain, both
under normal conditions and after damage to the nervous system."
Dr. Woolf carried out the study in collaboration with Mitchell
B. Max, M.D., of the National Institute of Dental and Craniofacial
Research (NIDCR) in Bethesda, Maryland, and colleagues at the National
Institute on Alcoholism Abuse and Alcoholism (NIAAA) and elsewhere.
Dr. Woolf's work was funded by the National Institute of Neurological
Disorders and Stroke (NINDS). The research team also received funding
from NIDCR, NIAAA, and other organizations.
The researchers originally identified GCH1 by preclinical
screening for genes that undergo significant changes in expression
after sciatic nerve injury. GCH1 is one of several genes
that code for enzymes needed to produce a chemical called tetrahydrobiopterin
(BH4). Previous studies have shown that BH4 is an essential ingredient
in the process that produces dopamine and several other nerve-signaling
chemicals (neurotransmitters). It also plays other important roles
in the body. However, this study is the first to show that GCH1
and BH4 play a role in pain.
The investigators tested the effects of GTP cyclohydrolase and
BH4 in several animal models of pain. They found that rats with
neuropathic pain (pain caused by nerve damage) had greatly increased
levels of GCH1 gene activity and BH4, and that injecting
a GTP cyclohydrolase inhibitor called 2,4-diamino-6-hydroxypyrimidine
(DAHP) alleviated hypersensitivity to pain in animal models of
both neuropathic pain and inflammatory pain. In contrast, injecting
BH4 greatly increased pain sensitivity.
Next, the researchers looked for GCH1 gene variations
in people. They found that a specific variant of the gene, identified
by combinations of one-base-pair changes in the DNA called single
nucleotide polymorphisms or SNPs, protected against development
of chronic post-surgical pain in people who had participated in
a study of surgical diskectomy for back pain. About 28 percent
of the people in the surgical study had at least one copy of the
pain-protective variant of the gene (people have two copies of
every gene). The researchers found that people with two copies
of the protective version of GCH1 had the lowest risk
of developing chronic pain, while those with just one copy had
an intermediate risk and those with no copies of the variant had
the highest risk.
The researchers then found that the gene variant also appeared
to reduce sensations of acute pain in normal volunteers, who had
been tested by NIH-supported scientists Dr. William Maixner at
the University of North Carolina and Dr. Roger Fillingim at the
University of Florida. Normal volunteers with two copies of the
protective gene variant were less sensitive to temporary pain induced
by pressure and other stimuli than those with one or no copies.
Analysis of blood cells from the people who had undergone back
surgery showed that, under normal conditions, the amounts of GTP
cyclohydrolase and BH4 were not significantly different in people
with and without the gene variant. When the cells were subjected
to a chemical that increases GCH1 gene activity, however,
the amount of gene activity increased much less in people with
the pain-protective variant of the gene than it did in other people.
The variation that affects pain sensitivity is in a region of
the gene that may control when the gene is switched on. This, coupled
with the results of the blood study, makes the researchers suspect
that the protective version of the gene is less likely to be switched
on during stressful conditions such as nerve damage and inflammation. "We
often hear about gene mutations that are harmful, but here is a
mutation that's actually protective," says Dr. Woolf.
The GTP cyclohydrolase inhibitor used in this study, DAHP, is
not very strong and is unlikely to be useful as a human drug, Dr.
Woolf says. Researchers are now looking for other substances that
might work as GTP cyclohydrolase inhibitor drugs in humans.
Screening people for the pain-protective gene variant could allow
doctors to identify people at high risk of developing chronic pain
before they undergo surgery, Dr. Woolf says. Doctors might then
be able to reduce the risk of chronic pain by providing more aggressive
pain relief or choosing less invasive surgical procedures for people
at high risk of chronic pain. Several studies have suggested that
specific pain drugs or combinations of drugs can reduce the risk
of chronic pain after surgery.
Dr. Woolf and his colleagues are now planning studies to define
exactly how GCH1 is switched on by nerve injury and inflammation
and how it regulates pain. They also hope to identify other gene
variants that affect pain sensitivity and the risk of chronic pain. "We
think this gene accounts for some of the inherited differences
in pain, but other genes may also play a role," Dr. Woolf says.
The NINDS, NIDCR, and NIAAA are components of the National
Institutes of Health (NIH) within the Department of Health and
Human Services. The NINDS (http://www.ninds.nih.gov)
is the nationís primary supporter of biomedical research on the
brain and nervous system. The NIDCR (http://www.nidcr.nih.gov)
is the nationís leading funder of research on oral, dental, and
craniofacial health. The NIAAA (http://www.niaaa.nih.gov/)
is the primary U.S. agency for conducting and supporting research
on the causes, consequences, prevention, and treatment of alcohol
abuse, alcoholism, and alcohol problems.
Disclosure: Dr. Woolf has an equity holding in a company,
Solace Pharmaceuticals., which has licensed technology from the
Massachusetts General Hospital related to this research.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.