UF Study: Neurotoxin Eliminates Pain-Transmitting Nerve Cells In Rats With Spinal Cord Injury
GAINESVILLE, Fla. — A potent neurotoxin can be used to zap rogue nerve cells responsible for triggering chronic pain after paralyzing spinal cord injury in rats, an approach scientists have labeled molecular neurosurgery, University of Florida researchers report in the online edition of Neuroscience Letters.
The neurotoxin acts on specific sites in the spinal cord, where it is incorporated into nerve cells, which then die. By eliminating these cells, researchers were able to significantly lengthen the time between injury and any signs of pain behavior as well as decrease the severity of pain.
The research is part of ongoing efforts to explore the mechanisms of pain after spinal cord injury. Surprisingly, up to 80 percent of people who suffer from spinal injury develop some form of excruciating chronic pain at or below the level of their paralysis, experts say. Many describe their discomfort as burning, stabbing or even electric.
“Most people think spinal cord injury results in a loss of sensations below the level of injury, but it turns out that spontaneous pain following spinal injury usually is referred to parts of the body below the level of injury, where there is no motor or sensory function,” said Robert P. Yezierski, director of UF’s Comprehensive Center for Pain Research. “Pain following spinal injury is a devastating consequence of injury. Many people would gladly exchange relief of pain with a lot of other potential cures, including the ability to walk.
“The unfortunate thing is we have no long-term effective treatments for this type of pain,” added Yezierski, who also is associated with UF’s McKnight Brain Institute and the College of Dentistry. “This is why we are trying to develop novel approaches. We think that molecular neurosurgery could potentially be an answer for this condition.”
The anatomy, the way cells function and the chemical language the spinal cord uses to fire messages to the brain all change after an injury. In a way, chronic pain after spinal cord injury is similar to phantom pain experienced by some patients after amputation, and scientists think the underlying mechanisms of these disorders may be similar.
“The rules that apply in the normal condition no longer apply in the injured state,” Yezierski said. “So we’re dealing with a totally different functional, structural and chemical entity following injury, and that’s been the biggest challenge – to figure out what those changes are in the injured spinal cord.”
UF researchers identified a population of nerve cells in the spinal cord essential to relaying messages to the brain responsible for the referred pain sensation many patients describe after spinal cord injury. The nerve cells are located in a region associated with pain processing, and each has a receptor on its surface that binds to a powerful pain transmitter known as substance P.
As part of the study, funded by a $1.2 million grant from the National Institutes of Health, scientists used a neurotoxin hooked to a compound that docks at receptors on the surface of nerve cells in the spinal cord.
They injected the neurotoxin into the area surrounding spinal cord injury in more than 60 rats, either at the time of injury or later, after the animals began exhibiting a grooming behavior associated with pain. After the neurotoxin was administered, researchers noted delays in the expected onset and severity of pain-associated excessive grooming behavior. Higher doses of the neurotoxin produced the most significant pain-relieving effect, although a significant response also was seen at a lower dose.
Researchers believe that once the protein complex containing the neurotoxin docks at the site, the cell allows it to enter. Inside the cell, the protein and the neurotoxin separate. The neurotoxin then initiates chemical changes that kill the cell.
“The results of the intervention have shown that this unique population of neurons definitely contribute to the onset and maintenance of the injury-induced pain behavior,” Yezierski said. “There’s reason to be optimistic that we now are identifying therapeutic targets and strategies of intervention that will hopefully lead to more effective therapies for the treatment of this condition. We hope the approach that was used to identify these neurons can be used clinically in individuals who have spinal cord injury pain. Efforts are now under way to develop a clinical trial for this particular approach.”
Similar studies conducted elsewhere have used the same molecular neurosurgery approach to successfully treat other types of pain originating from peripheral nerve damage or from inflammation. The UF study was the first to try the technique to treat pain of a central origin.
“Spinal cord injury is an extraordinarily complicated set of events that leads frequently to severe pain states that often are very difficult to manage,” said Tony Yaksh, a professor and vice chairman for research in anesthesiology at the University of California, San Diego.
“Dr. Yezierski’s paper looking at the effects of spinal delivery of this toxin promises a novel approach to an otherwise very difficult-to-manage disorder,” Yaksh said. “Of course, there’s a lot of work that remains to be done, but in one fell swoop it provides significant insight into the mechanisms of this disorder, that is to say, targeting this specific site for the toxin to act in the spinal cord, and it provides the possibility of a therapeutic intervention. We ourselves are involved in studying the safety of substance P-saporin in other animal models, and there is a good likelihood that this new peptide may in fact find its way into humans for therapeutic treatment of a variety of complicated pain states. Dr. Yezierski’s study seems to point directly to the importance of this mechanism in pain secondary to spinal cord injury.”