Unlike a broken arm or leg, a damaged spinal cord does not stop hurting once the body heals. An estimated 60 percent of those with spinal cord injuries suffer from chronic pain for which there is currently no treatment. At the PVA/EPVA Center, Marco A. Rizzo, M.D., Ph.D., assistant professor of neurology, and Sulayman Dib-Hajj, Ph.D., an associate research scientist, are part of a team that is developing the basis for drugs that will end post-spinal cord injury pain, again exploiting the properties of sodium channels.
After injury, the genes that produce some types of sodium channels are turned on, producing too many of these channels. The genes for other sodium channels are turned off, and these channels disappear. The work of Dr. Rizzo and Dr. Dib-Hajj suggests that this change is a root cause of pain. Unlike potassium channels, which block the transmission of impulses after injury, sodium channels produce an abnormal "repetitive firing" of impulses. The challenge now is to identify the varying types of sodium channels and determine how to inhibit those that trigger pain. Two dozen sodium channels have been identified in organisms from jellyfish to humans, and scientists believe there may be many more. Using computerized sequence analysis, Dr. Dib-Hajj has studied their development over the course of evolution, charting the differences that are evident between species. "We can learn a lot by comparing the sequences," he explains. "The idea is that if function is conserved over evolutionary time, we may be able to identify a similarly conserved amino acid sequence and determine experimentally if it underlies that function of the protein. Which amino acid residues cause the sodium channel to open and close or to be fast or slow? These are important issues for rational drug design that targets specific channels."
In addition to pain, most patients with spinal cord injuries and MS experience debilitating muscle spasms caused by damage to axons in the spinal cord. Scientists at Yale are examining the physiological basis for spasticity and are developing the basis for new drugs to alter the opening of sodium channels or modulate the level of GABA, a neurotransmitter produced by the body that prevents hyperactive uninhibited nerve activity.