Gene Variation Affects Pain Sensitivity And Risk Of Chronic Pain

[Guest guest]

Gene Variation Affects Pain Sensitivity And Risk Of Chronic Pain

http://www.medicalnewstoday.com/medicalnews.php?newsid=54896

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 chronic

pain.

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.*

" 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 B.

Max, M.D., of the National Institute of Dental and Craniofacial

Research (NIDCR) in Bethesda, land, 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. Maixner at the

University of North Carolina and Dr. 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.