When people think of spinal cord injury, they tend to think of paralysis. But a spinal cord injury can also cause debilitating muscle spasms. Although the drug baclofen can control these spasms, many patients cannot tolerate its side effects, which include general sedation and dizziness. A new study sheds light on how a spinal cord injury leads to spasms, and on the promise of more precisely targeted drugs with fewer side effects.
The study focuses on what happens to muscle-controlling nerve cells (motor neurons) after a spinal cord injury. In an intact spinal cord, these neurons are under the command of signals from the brain. Some signals tell the motor neurons to fire, which causes their associated muscles to contract. Other signals silence the motor neurons and cause muscle relaxation.
After a spinal cord injury, both kinds of signals are interrupted. The motor neurons are not under the brain’s control anymore, but they continue to fire spontaneously, leading to spasms. The new study explains how this spontaneous activity occurs.
The research was led by David Bennett, Ph.D., and Karim Fouad, Ph.D., neuroscientists at the University of Alberta in Canada. Partial funding came from the National Institute of Neurological Disorders and Stroke. Dr. Bennett’s lab has a novel system for studying spinal cord injuries in rats; it is the only system in the world that enables researchers to precisely control the environment surrounding the injured spinal cord and simultaneously record the electrical activity of individual spinal neurons.
The researchers theorized that after an injury, spasticity could occur because a small number of intact fibers in the spinal cord continue to produce serotonin – a brain-derived chemical that excites motor neurons. Yet, in rats with spinal cord injury, there was no evidence of residual serotonin. Instead, the motor neurons below the injury began producing higher levels of a serotonin receptor that is persistently “on,” even in the absence of serotonin.
“A receptor is supposed to receive by definition,” said Dr. Bennett in an interview with Nature Medicine,* where the study was published. “The analogy would be a telephone starting to talk without anyone talking into it,” he said.
The research comes full circle with prior clinical studies of cyproheptadine, a drug that blocks many different types of serotonin receptors. Years ago, cyproheptadine was found to reduce spasticity in patients with spinal cord injury, but it can also lead to overeating and obesity. Plus, until now, no one understood how it worked.
Dr. Bennett and his colleagues tested cyproheptadine in their rat model of spinal cord injury, and found that it reduces spontaneous motor neuron activity. They also tested cyproheptadine in several people with spinal cord injury. By monitoring spasms in the patients’ leg muscles using electromyography (EMG), the team confirmed that the drug acts through the same mechanism in humans as it does in rats.
The experimental drug SB206553, which is more specific than cyproheptadine for the subtype of serotonin receptors found on motor neurons, also reduced spasms in rats. A drug like SB206553 might be the answer to the side effects observed with cyproheptadine and baclofen, Dr. Bennett said.
SB206553 must be injected directly into the spinal cord, and has not yet been tested in humans.
And there is another important cautionary note. Researchers have long recognized that the spontaneous neuronal activity and spasms that follow a spinal cord injury are not uniformly harmful. For people with partial spinal cord injuries, these changes can actually help maintain muscle tone and support limited movements. Dr. Bennett and his team confirmed that when rats with a partial spinal cord injury received a high dose of SB206553, they had poor locomotor recovery compared to injured but untreated rats. This means that careful dosing will be just as important as finding a drug that hits the right target.
-By Daniel Stimson, Ph.D.