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Science 330 (6009): 1400-1404

Copyright © 2010 by the American Association for the Advancement of Science

Alleviating Neuropathic Pain Hypersensitivity by Inhibiting PKM{zeta} in the Anterior Cingulate Cortex

Xiang-Yao Li,1,2,* Hyoung-Gon Ko,3,* Tao Chen,1,2,* Giannina Descalzi,1 Kohei Koga,1 Hansen Wang,1 Susan S. Kim,1 Yuze Shang,1 Chuljung Kwak,3 Soo-Won Park,3 Jaehoon Shim,2,3 Kyungmin Lee,3,4 Graham L. Collingridge,2,5 Bong-Kiun Kaang,2,3,{dagger} Min Zhuo1,2,{dagger}

Abstract: Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKM{zeta}) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKM{zeta} in the ACC, and inhibiting PKM{zeta} by a selective inhibitor, {zeta}-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKM{zeta} in the ACC acts to maintain neuropathic pain. PKM{zeta} could thus be a new therapeutic target for treating chronic pain.

1 Department of Physiology, Faculty of Medicine, Center for the Study of Pain, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
2 Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151 747, Korea.
3 National Creative Research Initiative Center for Memory, Department of Biological Sciences, College of Natural Sciences, Seoul National University, San 56-1 Silim-dong, Gwanak-gu, Seoul 151-747, Korea.
4 Department of Anatomy, School of Medicine, Kyungpook National University, 2-101 Dongin-Dong, Daegu 700-422, Korea.
5 Medical Research Council (MRC) Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: kaang{at} (B.-K.K.); min.zhuo{at} (M.Z.)

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