Researchers Identify Key Protein Involved In Neuropathic Pain

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Many people suffering from neuropathic pain appear normal, but are in agony experiencing lightning-like pain known as allodynia.

This type of pain can alter perception to a point where previously innocuous or even pleasurable stimuli applied to the skin or tissues become extremely painful. It may be experienced after nerve injury or from diseases that affect peripheral nerve function such as diabetes, shingles, or cancer.

After a peripheral nerve injury there is a biophysical change in spinal cord cells called microglia. Microglia are typically considered to be immune cells in the nervous system, but have now been proven to be involved in neuropathic pain.

"We knew that microglia had to communicate with nerve cells in the pain-processing network in the spinal cord. However the mechanism for this communication was not known," said Dr. Michael Salter, co-principal investigator, senior scientist at SickKids, professor of Physiology at the University of Toronto (U of T), and director of the U of T Centre for the Study of Pain. "We discovered that the microglia talk to the nerves cells by releasing Brain-Derived Neurotropic Factor (BDNF)."

When BDNF was injected into the spinal cords of normal mice it resulted in allodynia. When the team made manipulations to block or intercept BDNF signaling from the microglia the in nerve-injured mice the allodynia was reversed.

"We established that the microglia cause chloride ions to increase inside the nerve cells and that BDNF is the mystery mediator," said Dr. Yves De Koninck, co-principal investigator, professor, Department of Psychiatry, Université Laval and director of the Division of Cellular Neurobiology at the Centre de recherche Université Laval Robert-Giffard. "Thus, not only did we discover that BDNF is the chemical mediator, but we also determined how BDNF works."

By a still unknown mechanism, nerve injury results in activation of P2X4 receptors on the microglia, which causes the release of BDNF. BDNF then disrupts inhibition in the spinal cord, which causes spinal relay neurons to send an abnormal signal to pain-processing neural networks in the brain, ultimately causing the experience of aberrant pain.

The research team hopes that this new information on neuropathic pain can be applied to diagnostics. "Effective pain diagnosis is nearly as big a challenge as developing effective pain therapeutics," added Dr. Salter, also Canada Research Chair in Neuroplasticity and Pain. "The gold standard for diagnosing neuropathic pain is history and physical examination. But many people want objective proof that something is pathophysiologically different. We are hoping to develop a probe that can measure the response of microglia in people with peripheral nerve injury."

The team is also looking for ways to devise new kinds of therapeutics, as there is not presently any effective treatment for neuropathic pain.

"This is an important discovery for the millions of Canadians who suffer from debilitating chronic pain that cannot currently be treated. The cost to society is equally devastating and is estimated in the billions of dollars annually," said the Honourable Michael H. Wilson, chair of NeuroScience Canada, one of the funders of this research through the Brain Repair Program, which includes $1.5 million to the team led by Dr. Michael Salter. NeuroScience Canada's funding partners on the team grant led by Dr. Salter include the Canadian Institutes of Health Research and the Ontario Neurotrauma Foundation.

"With the work of Drs. Salter and De Koninck, we can now focus the research on developing drugs that will target the class of cells responsible for chronic pain. This represents an important shift that could soon provide patients with effective treatments and allow them to be active again in our society," added Mr. Wilson.

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Other members of the research team include co-lead authors Dr. Simon Beggs of SickKids and Dr. Jeffrey Coull of McGill University, Dominic Boudreau, Dominick Bovin and Dr. Claude Gravel of Université Laval, Drs. Makoto Tsuda and Kazuhide Inoue of Kyushu University, Japan.

This research was supported by the Canada Research Chairs Program, the Canadian Institutes of Health Research, Fonds de la recherche en santé du Québec, Neuroscience Canada and SickKids Foundation.