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November 16, 2008

Researchers discover a novel therapy for chronic pain by blocking an intracellular protein interaction in the central nervous system

TORONTO – Researchers at The Hospital for Sick Children (SickKids) and the University of Toronto have developed a novel peptide for treating pain by blocking an intracellular protein interaction in the central nervous system. This research is reported online on November 16 in the journal Nature Medicine.

This research was made possible with the support of a $1.75-million NeuroScience Canada Brain Repair Program team grant that enabled Dr. Michael Salter and his team to join with other scientists from across Canada to work together and fast track their research.

“A major roadblock in chronic pain research has been translating knowledge of biological mechanisms into therapeutic approaches that are both effective and safe,” said Dr. Salter, the study's principal investigator, Senior Scientist and Head of the Program in Neurosciences and Mental Health at SickKids, Professor of Physiology and Director of the University of Toronto Centre for the Study of Pain, International Research Scholar of the Howard Hughes Medical Institute and holder of a Canada Research Chair. “We were able to move past it with our discovery of a novel peptide-based therapeutic approach, which may lead to a new and previously unsuspected way of treating chronic pain.”

Chronic pain hypersensitivity is known to involve N -methyl-D-aspartate receptors (NMDARs), a main type of receptor mediating communication between nerve cells in the brain and spinal cord. However, treating chronic pain through the use of NMDAR blocking drugs is limited because NMDARs are essential for many key physiological functions, including breathing and cognition. Salter's team discovered that pain hypersensitivity depends upon amplification of the function of NMDARs by an enzyme known as Src.

Using mouse models, the team designed a peptide that is able to prevent the action of Src to amplify NMDAR function. This was achieved by designing the peptide to disrupt the interaction between two proteins, Src and NADH dehydrogenase subunit 2 (ND2), which anchors Src to NMDAR. Salter's team shows that the peptide selectively inhibits the amplification of NMDAR that produces chronic pain, without affecting psychological functions of the receptor.

“The peptide has key characteristics of an ideal analgesic in reducing pain in models of both chronic inflammatory and neuropathic pain, the two main types of chronic pain,” says Dr. Xue Jun Liu, the study's lead author, a post-doctoral fellow at SickKids and the University of Toronto . “This is critical because it can be difficult to distinguish inflammatory versus neuropathic pain, as patients often have symptoms of both types, and presently available analgesics may only be effective against one type or the other.”

Chronic pain is a pervasive, insidious and often devastating problem that affects both children and adults. According to the Canadian Pain Survey, one in six Canadians (16 per cent) live with constant pain, and one in five (20 per cent) experience pain daily. The total annual economic cost of pain is estimated to be $40 billion in Canada alone. However, the impact of chronic pain should not be viewed simply in economic terms. Chronic pain has a major detrimental effect on the quality of life of the millions of chronic pain sufferers and their families worldwide.

Other members of the research team were Jeffrey R. Gingrich, Mariana Vargas-Caballero, Yi Na Dong, Ameet Sengar, Simon Beggs, Szu-Han Wang, Hoi Ki Ding and Paul W. Frankland, all from SickKids.

This research was also supported by the Canadian Institutes of Health Research, the Ontario Neurotrauma Foundation, the Krembil Foundation, and SickKids Foundation.

Founded in 1998, NeuroScience Canada (NSC) is a national non-profit organization that develops and supports collaborative, multidisciplinary, multi-institutional research across the neurosciences. Through partnering with the public, private and voluntary sectors, NeuroScience Canada connects the knowledge and resources available in this area to maximize the output of Canada 's world-class scientists and researchers.

The mission of NeuroScience Canada 's Brain Repair Program™ is to accelerate “transformative” research to discovery and to the development of new treatments and therapies for neurological and psychiatric diseases and disorders. NSC is achieving this by funding teams of investigators from various disciplines and institutions that have the best chance of producing rapid progress in repairing the brain. In the first phase of the Brain Repair Program, NSC and its donors and partners are investing $8 million in research teams.

Salter is the lead investigator of the Brain Repair Program project titled, Transforming research on chronic pain in Canada . NeuroScience Canada has invested $1.75 million in this project for this team to conduct breakthrough work in the area of neuroscience.

The Hospital for Sick Children (SickKids), affiliated with the University of Toronto, is Canada's most research-intensive hospital and the largest centre dedicated to improving children's health in the country. As innovators in child health, SickKids improves the health of children by integrating care, research and teaching. Our mission is to provide the best in complex and specialized care by creating scientific and clinical advancements, sharing our knowledge and expertise and championing the development of an accessible, comprehensive and sustainable child health system. For more information, please visit www.sickkids.ca . SickKids is committed to healthier children for a better world.

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