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Researchers discover on-off switch for chronic pain

Chronic pain affects approximately 48 million people in the U.S. and current medications are either largely ineffective or have serious side effects.

But researchers from Columbia University Medical Center have discovered a protein in nerve cells that acts as a switch for chronic pain, and have applied for a patent to develop a new class of drugs that will block chronic pain by turning this switch off. The discovery is published on the website of the journal Neuroscience, and will appear in the publication's August issue.

Most prior attempts at alleviating chronic pain have focused on the "second order" neurons in the spinal cord that relay pain messages to the brain. It's difficult to inhibit the activity of these neurons with drugs, though, because the drugs need to overcome the blood-brain barrier. Instead, the CUMC researchers have focused on the more accessible "first order" neurons in the periphery of our body that send messages to the spinal cord.

Pain becomes chronic when the activity of first and second order neurons persists after damaged neuron heals or the tissue inflammation subsides. It's been known for years that for chronic pain to persist, a master switch must be turned on inside the peripheral neurons, though until now the identity of this switch remained a mystery. Richard Ambron, Ph.D., professor of cell biology, and Ying-Ju Sung, Ph.D., assistant professor, both in the department of Anatomy and Cell Biology, have now discovered that the switch is an enzyme called protein kinase G (PKG).

"We're very optimistic that this discovery and our continued research will ultimately lead to a novel approach to pain relief for the millions suffering from chronic pain," said Dr. Ambron.

The researchers found that upon injury or inflammation, the PKG is turned on and activated. Once activated, these molecules set off other processes that generate the pain messages. As long as the PKG remains on, the pain persists. Conversely, turning the PKG off relieves the pain, making PKG an excellent target for therapy.

Dr. Ambron and Dr. Sung have applied for a patent for the pathway that turns on the PKG, as well as several molecules that inhibit it.

Based on the 2004 Americans Living with Pain Survey, 72 percent of people with chronic pain have lived with it for more than three years, including a third who have lived with pain for more than a decade. Yet nearly half of people with pain do not consult a physician for several months or longer, despite the impact the pain has on their lives.

The worldwide painkiller market was worth $50 billion in 2005 and is expected to increase to $75 billion by 2010 and $105 billion by 2015. But none of the existing drugs on the market are adequate to deal with chronic pain. Cox-2 inhibitors carry severe risk of side effects, opioids are highly addictive, Tylenol is ineffective for chronic pain, and other pain drugs cause significant drowsiness.

Craig LeMoult | EurekAlert!
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