Cortical GluK1 kainate receptors modulate scratching in adult mice

Authors

  • Giannina Descalzi,

    1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
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  • Tao Chen,

    1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
    2. Center for Neuron and Disease, Frontier Institutes of Life Science, and Science and Technology, Xi'an Jiaotong University, Xian, Shanxi, China
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  • Kohei Koga,

    1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
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  • Xiang-Yao Li,

    1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
    2. Center for Neuron and Disease, Frontier Institutes of Life Science, and Science and Technology, Xi'an Jiaotong University, Xian, Shanxi, China
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  • Kaori Yamada,

    1. Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
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  • Min Zhuo

    Corresponding author
    1. Center for Neuron and Disease, Frontier Institutes of Life Science, and Science and Technology, Xi'an Jiaotong University, Xian, Shanxi, China
    • Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, University of Toronto Center for the study of Pain, Toronto, Ontario, Canada
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Address correspondence and reprint requests to Min Zhuo, Department of Physiology, University of Toronto, Medical Sciences Bldg, Rm 3342, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. E-mail: min.zhuo@utoronto.ca

Abstract

Recent investigations into the mechanisms mediating itch transmission have focused on spinal mechanisms, whereas few studies have investigated the role of the cerebral cortex in itch-related behaviors. Human imaging studies show that several cortical regions are active in correspondence with itch, including the anterior cingulate cortex (ACC). We present here evidence of cortical modulation of pruritogen-induced scratching behavior. We combine pharmacological, genetic, and electrophysiological approaches to show that cortical GluK1-containing kainate (KA) receptors are involved in scratching induced by histamine and non-histamine-dependent itching stimuli. We further show that scratching corresponds with enhanced excitatory transmission in the ACC through KA receptor modulation of inhibitory circuitry. In addition, we found that inhibiting GluK1-containing KA receptors in the ACC also reduced behavioral nociceptive responses induced by formalin. Our results reveal a new role of the cortex in pruritogen-induced scratching.

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Cortical contribution to pruritogen-induced scratching is shown in an animal model. Through a combination of pharmacological, genetic, and electrophysiological data, we show that cortical GluK1-containing kainate receptors (KAR) are involved in pruritogen-induced scratching. Peripheral application of itching stimuli activates excitatory afferents projecting to ACC layer II/III pyramidal neurons, initiating presynaptic glutamate (Glu) release which activates postsynaptic AMPA receptors. Simultaneously, presynaptic Glu activates presynaptic KAR located on inhibitory neurons, thereby modulating evoked GABA release and affecting the attenuation of the postsynaptic response.

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