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October 30, 2006
Volume 84, Number 44
p. 13

Neurochemistry

New Pathway To Pain Medications

Gene, enzyme, and small molecule control pain sensitivity

Stu Borman

A gene, the enzyme it encodes, and a small molecule it helps produce have been found to control sensitivity to chronic pain in people. The study provides new molecular targets for medications that could alleviate chronic pain, a condition for which new drugs are urgently needed.

Courtesy of Ryoji Masui/Osaka University
The enzyme GCH1 (above) is part of a pain-sensitivity-controlling pathway that produces BH4 (structure at right).

Tens of millions of people in the U.S. suffer chronic pain. The condition may start with an injury, spinal disc problem, or a disease like diabetes, and it persists for weeks, months, or years. Some patients respond only partially or not at all to current drugs, which can cause serious side effects, such as sedation, nausea, and cognitive changes.

Professor of anesthesia research Clifford J. Woolf of Massachusetts General Hospital, Boston, and Harvard Medical School and coworkers have now identified a gene that affects sensitivity to chronic pain (Nat. Med., DOI: 10.1038/nm1490). Expression of the gene increases when animals receive pain stimuli, and blocking these increases prevents the animals from developing chronic pain.

The gene codes for an enzyme called GTP cyclohydrolase-1 (GCH1), and the study suggests that inhibiting the activity of this enzyme might help prevent or treat chronic pain. GCH1 is one of several enzymes that produce tetrahydrobiopterin (BH4), an essential cofactor for the production of neurotransmitters such as catecholamines, serotonin, and nitric oxide, and the study showed that directly increasing BH4 levels boosts animals' sensitivity to pain.

In human studies, Woolf and coworkers found that 20 to 25% of people have at least one copy of a variant of the GCH1 gene that protects from pain and 3% have two copies. Those with one copy had lower than normal risk of developing postsurgical chronic pain, and patients with two had the lowest risk. The presence of the gene variant in normal volunteers was also found to reduce sensitivity to acute pain.

The researchers speculate that using an enzyme inhibitor to reduce excess levels of BH4 might be an effective way to treat pain with few side effects. One wouldn't want to remove all BH4 from the body, but they believe inhibitors could be developed to deplete only pain-induced excesses of the compound. Woolf is associated with Solace Pharmaceuticals, Boston, which has licensed the findings and is pursuing GCH1 inhibitors as potential pain medications.

Neuroscientist Linda Porter, a program director at the National Institute of Neurological Disorders & Stroke who manages a portfolio of pain research grants, including one for the Woolf group's study, says the work is "a nice blend of animal and human data that supports the idea that there are genetic components that would make some people more susceptible than others to developing chronic pain states." The new study "also opens up some avenues for new therapy development," she says.

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