Xiang-Yao Li1,2,*, Hyoung-Gon Ko3,*, Tao Chen1,2,*, Giannina Descalzi1, Kohei Koga1, Hansen Wang1, Susan S. Kim1, Yuze Shang1, Chuljung Kwak3, Soo-Won Park3, Jaehoon Shim2,3, Kyungmin Lee3,4, Graham L. Collingridge2,5, Bong-Kiun Kaang2,3,† and Min Zhuo1,2,†
1Department of Physiology, Faculty of Medicine, Center for the Study of Pain, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
2Department of Brain and Cognitive Sciences, Seoul National University, Seoul 151 747, Korea.
3National 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.
4Department of Anatomy, School of Medicine, Kyungpook National University, 2-101 Dongin-Dong, Daegu 700-422, Korea.
5Medical Research Council (MRC) Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, UK.
†To whom correspondence should be addressed.
* These authors contributed equally to this work.
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 (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation. Microinjection of ZIP into the ACC blocked behavioral sensitization. These results suggest that PKMζ in the ACC acts to maintain neuropathic pain. PKMζ could thus be a new therapeutic target for treating chronic pain.
Received for publication 3 May 2010.
Accepted for publication 18 October 2010.