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BUT MICHAEL W. SALTER, AN HHMI INTERNATIONAL RESEARCH SCHOLAR AT TORONTO'S HOSPITAL FOR SICK CHILDREN, MANAGED IN JUST 6 YEARS TO PROVE THAT THE TRADITIONAL THINKING BEHIND CHRONIC PAIN WAS, IF NOT WRONG, AT LEAST NOT COMPLETELY RIGHT.
Pain is usually a warning. It alerts us to injuries or potential damage to the body. But sometimes the nervous system itself is the cause of pain. Such “neuropathic” pain, which occurs when peripheral nerves are damaged from surgery, disease, or infection, can render people so sensitive to normal stimuli that everyday activities—wearing shoes, for example—can be excruciating. Sadly, modern medicine does not have much to offer these patients. Current therapies offer relief to fewer than half of patients, and their pain is usually reduced by no more than 25 percent.
Until recently, the accepted dogma was that malfunctioning neurons were completely responsible for neuropathic pain. My colleagues and I have now shown that while neurons are indeed involved, they have co-conspirators: the spinal cord's microglial cells. It turns out that, among their many jobs in immune surveillance in the nervous system, microglia serve as signaling cells that provide information to neurons. We've demonstrated this relationship by proving its inverse: by inhibiting a receptor, called P2X4, on the microglia, we were able to alleviate induced neuropathic pain in rats.
Unfortunately, the agent we used to block the receptor was not sufficiently stable to be a good candidate for a therapeutic agent for humans. But knowing that microglia are key to neuropathic pain gives us other approaches to pursue. Once activated, this pain pathway is like a set of dominoes. When the first one falls, it knocks down the next one, and so on, until reaching the pain networks in the brain, which is when the hurt begins.
So, our theory is that neuropathic pain would be eased if we could pharmacologically interfere with just one of those myriad intermediate steps—the dominoes—in the spinal cord between the beginning of the pathway (activation of the P2X4 receptor on the microglia) and the end (suppression of a transporter known as KCC2 on spinal-cord neurons that send the pain signals on to the brain). Sorting out this relationship between microglia and neurons is the current emphasis of our research.
We have already experimented with some attractive targets. One of them is brain-derived neurotrophic factor (BDNF). Our team has shown that activation of microglia's P2X4 receptors causes the release of BDNF, which then mediates the signaling between the microglia and neurons that leads to pain hypersensitivity. To interfere with this process, we have used antibodies that successfully block the action of BDNF. But they have to be injected directly into the spinal cord—a less-than-practical approach.
Photo: Finn O'Hara
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